Materiały źródłowe

• #1 Molecular Mechanism and Role of Japanese Encephalitis Virus Infection in Central Nervous System-Mediated Diseases

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9781168/

  The Japanese encephalitis virus (JEV) is the most common cause of neurodegenerative disease in Southeast Asia and the Western Pacific region; approximately 1.15 billion people are at risk, and thousands suffer from permanent neurological disorders across Asian countries, with 1015 thousand people dying each year. JEV crosses the blood-brain barrier (BBB) and forms a complex with receptors on the surface of neurons. GRP78, Src, TLR7, caveolin-1, and dopamine receptor D2 are involved in JEV binding and entry into the neurons, and these receptors also play a role in carcinogenic activity in cells. […] JEV binds to GRP78, a member of the HSP70 overexpressed on malignant cells to enter neurons, indicating a higher chance of JEV infection in cancer patients. However, JEV enters human brain microvascular endothelial cells via an endocytic pathway mediated by caveolae and the ezrin protein and also targets dopamine-rich areas for infection of the midbrain via altering dopamine levels. In addition, JEV complexed with CLEC5A receptor of macrophage cells is involved in the breakdown of the BBB and central nervous system (CNS) inflammation. CLEC5A-mediated infection is also responsible for the influx of cytokines into the CNS.

• #2 Molecular Mechanism and Role of Japanese Encephalitis Virus Infection in Central Nervous System-Mediated Diseases

  https://www.mdpi.com/1999-4915/14/12/2686

  The Japanese encephalitis virus (JEV) is the most common cause of neurodegenerative disease in Southeast Asia and the Western Pacific region; approximately 1.15 billion people are at risk, and thousands suffer from permanent neurological disorders across Asian countries, with 10–15 thousand people dying each year. JEV crosses the blood-brain barrier (BBB) and forms a complex with receptors on the surface of neurons. GRP78, Src, TLR7, caveolin-1, and dopamine receptor D2 are involved in JEV binding and entry into the neurons, and these receptors also play a role in carcinogenic activity in cells. JEV binds to GRP78, a member of the HSP70 overexpressed on malignant cells to enter neurons, indicating a higher chance of JEV infection in cancer patients. However, JEV enters human brain microvascular endothelial cells via an endocytic pathway mediated by caveolae and the ezrin protein and also targets dopamine-rich areas for infection of the midbrain via altering dopamine levels. In addition, JEV complexed with CLEC5A receptor of macrophage cells is involved in the breakdown of the BBB and central nervous system (CNS) inflammation. CLEC5A-mediated infection is also responsible for the influx of cytokines into the CNS. In this review, we discuss the neuronal and macrophage surface receptors involved in neuronal death.

• #3 Pathogenesis and Host Immune Response during Japanese Encephalitis Virus Infection | IntechOpen

  https://www.intechopen.com/chapters/77546

  Japanese Encephalitis Virus (JEV) is a mosquito borne flavivirus infection. Once JEV makes its entry into blood, it infects monocytes wherein the viral replication peaks up without any cell death and results in production of TNF-. One of the most characteristics pathogenesis of JEV is the breaching of blood brain barrier (BBB). JEV propagation occurs in neurons that results in neuronal cell death as well as dissemination of virus into astrocytes and microglia leading to overexpression of proinflammatory cytokines. JEV infection results in host cells mediated secretion of various types of cytokines including type-1 IFN along with TNF- and IFN-. Molecule like nitrous oxide (NO) exhibits antiviral activities against JEV infection and helps in inhibiting the viral replication by blocking protein synthesis and viral RNA and also in virus infected cells clearance.

• #4 Pathogenesis and Host Immune Response during Japanese Encephalitis Virus Infection | IntechOpen

  https://www.intechopen.com/online-first/pathogenesis-and-host-immune-response-during-japanese-encephalitis-virus-infection

  Japanese Encephalitis Virus (JEV) is a mosquito borne flavivirus infection. Transmission of JEV starts with the infected mosquito bite where human dermis layer act as the primary site of infection. Once JEV makes its entry into blood, it infects monocytes wherein the viral replication peaks up without any cell death and results in production of TNF-. One of the most characteristics pathogenesis of JEV is the breaching of blood brain barrier (BBB). JEV propagation occurs in neurons that results in neuronal cell death as well as dissemination of virus into astrocytes and microglia leading to overexpression of proinflammatory cytokines. […] Molecule like nitrous oxide (NO) exhibits antiviral activities against JEV infection and helps in inhibiting the viral replication by blocking protein synthesis and viral RNA and also in virus infected cells clearance.

• #5 Pathogenesis and Host Immune Response during Japanese Encephalitis Virus Infection | IntechOpen

  https://www.intechopen.com/chapters/77546

  Japanese Encephalitis Virus (JEV) is a mosquito borne flavivirus infection. Once JEV makes its entry into blood, it infects monocytes wherein the viral replication peaks up without any cell death and results in production of TNF-. One of the most characteristics pathogenesis of JEV is the breaching of blood brain barrier (BBB). JEV propagation occurs in neurons that results in neuronal cell death as well as dissemination of virus into astrocytes and microglia leading to overexpression of proinflammatory cytokines. JEV infection results in host cells mediated secretion of various types of cytokines including type-1 IFN along with TNF- and IFN-. Molecule like nitrous oxide (NO) exhibits antiviral activities against JEV infection and helps in inhibiting the viral replication by blocking protein synthesis and viral RNA and also in virus infected cells clearance.

• #6 Japanese encephalitis | MedLink Neurology

  https://www.medlink.com/articles/japanese-encephalitis

  Japanese encephalitis is caused by the flavivirus Japanese encephalitis virus, which has a small (50 nm) lipoprotein envelope surrounding a nucleocapsid comprising of core protein and 11 KB single stranded RNA (3800 kD). […] In endemic areas, humans become infected with Japanese encephalitis virus after mosquito bites. The Japanese encephalitis virus multiplies locally and in regional nodes. After a phase of transient viremia, invasion of the central nervous system occurs via hematogenous spread. In the neurons, the virus replicates and matures in the neuronal secretory system, mainly the rough endoplasmic reticulum and Golgi apparatus, eventually destroying these structures. […] At autopsy, CNS findings in Japanese encephalitis reflect the inflammatory response to widespread neuronal infection with the virus. The thalamus, basal ganglia, midbrain, cerebellum, and anterior horns of the spinal cord are heavily affected, providing anatomical correlates for the tremor, dystonias, and flaccid paralysis that characterize the disease.

• #7 Pathogenesis and Host Immune Response during Japanese Encephalitis Virus Infection | IntechOpen

  https://www.intechopen.com/chapters/77546

  One of the most characteristics pathogenesis of JEV is the breaching of BBB. Neuron being the most important target cell during JEV however, when the infection gets into CNS, along with the neuronal cells, astrocytes also gets infected, which is a constituent of BBB and an important part of CNS. Astrocytes are also considered to be helping in the transmission of JEV to the cerebrospinal fluid from peripheral tissues. The microglial cell that is considered to be the resident immune cells/macrophage of CNS is also infected by JEV. Microglial cells play a very significant role in CNS during the JEV infection via acting as a virus reservoir. Upon activation microglia produces proinflammatory cytokines like TNF-alpha and IL-6, which induce death of neuronal cell. […] The pathogenesis of JEV needs to be explored at dual phases in human which initiates at the peripheral tissues and then, involvement of central nervous system (CNS). JEV propagation occurs in neurons that results in neuronal cell death. Neuronal cell death occurs via two mechanism; direct and indirect neuronal killing. Direct killing involves the JEV propagation inside the neuronal cells that results in cell death and indirect killing involves aggressive and intense inflammatory responses leading to up-regulation of inflammatory cytokines and reactive oxygen species that causes death of neurons. […] In order to prevent the JEV pathogenesis, virus clearance from the peripheral nervous tissues during the initial phase of infection is crucial for designing effective therapy.

• #8 Pathogenesis and Host Immune Response during Japanese Encephalitis Virus Infection | IntechOpen

  https://www.intechopen.com/online-first/pathogenesis-and-host-immune-response-during-japanese-encephalitis-virus-infection

  JEV propagation occurs in neurons that results in neuronal cell death. Neuronal cell death occurs via two mechanism; direct and indirect neuronal killing. Direct killing involves the JEV propagation inside the neuronal cells that results in cell death and indirect killing involves aggressive and intense inflammatory responses leading to up-regulation of inflammatory cytokines and reactive oxygen species that causes death of neurons. […] In order to prevent the JEV pathogenesis, virus clearance from the peripheral nervous tissues during the initial phase of infection is crucial for designing effective therapy. […] The initial step focuses on the inhibition or on limiting the spread of virus to any new cells. In addition, already infected cells are then either eliminated or replication of JEV is suppressed permanently.

• #9 Japanese Encephalitis – Viral Diseases – Infectious Diseases – Diseases – McMaster Textbook of Internal Medicine

  https://empendium.com/mcmtextbook/chapter/B31.II.18.1.21.

  1. Pathogenesis: Initially the virus replicates in cells at the site of the mosquito bite (ie, skin) and in local lymph nodes. This is followed by the viremic phase with transient inflammatory lesions in extraneural tissues such as the heart, lungs, liver, and reticuloendothelial system. Some patients have a neuroinfection; since JEV replicates in endothelial cells, a significant part of the central nervous system (CNS) may be involved, including the thalamus, basal ganglia, brainstem, cerebellum (with damage to Purkinje cells), hippocampus, and cerebral cortex. Apart from neurons the virus also attacks other cells in the CNS, including astrocytes and microglial cells, which may cause damage to the blood-brain barrier.

• #10 Molecular pathogenesis of Japanese encephalitis and possible therapeutic strategies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9162114/

  JEV infection alters the expression of various host proteins, which can have either anti-viral or pro-viral activity. […] GRP78 interacts with domain III of the JEV envelope protein, which is required for entry of JEV into the host cell. It is also involved in the replication of the viral genomic RNA and viral protein synthesis. […] The binding of JEV to the host cell occurs in two stages: (i) Initial binding to attachment factors and (ii) specific binding to endocytic receptors. […] The receptor-mediated interaction between JEV and the host cell is not fully understood. However, some studies have shown that receptors such as HSP70 (N2a cell receptor), CLEC5A (C-type lectin receptor), TIM/TAM phosphatidylserine receptor, GRP78, D2 receptor, and v3 (a glycoprotein of the integrin family) may assist in the entry of JEV into the host cell via endocytosis.

• #11 Molecular pathogenesis of Japanese encephalitis and possible therapeutic strategies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9162114/

  JEV infection alters the expression of various host proteins, which can have either anti-viral or pro-viral activity. […] GRP78 interacts with domain III of the JEV envelope protein, which is required for entry of JEV into the host cell. It is also involved in the replication of the viral genomic RNA and viral protein synthesis. […] The binding of JEV to the host cell occurs in two stages: (i) Initial binding to attachment factors and (ii) specific binding to endocytic receptors. […] The receptor-mediated interaction between JEV and the host cell is not fully understood. However, some studies have shown that receptors such as HSP70 (N2a cell receptor), CLEC5A (C-type lectin receptor), TIM/TAM phosphatidylserine receptor, GRP78, D2 receptor, and v3 (a glycoprotein of the integrin family) may assist in the entry of JEV into the host cell via endocytosis.

• #12 Molecular pathogenesis of Japanese encephalitis and possible therapeutic strategies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9162114/

  JEV infection alters the expression of various host proteins, which can have either anti-viral or pro-viral activity. […] GRP78 interacts with domain III of the JEV envelope protein, which is required for entry of JEV into the host cell. It is also involved in the replication of the viral genomic RNA and viral protein synthesis. […] The binding of JEV to the host cell occurs in two stages: (i) Initial binding to attachment factors and (ii) specific binding to endocytic receptors. […] The receptor-mediated interaction between JEV and the host cell is not fully understood. However, some studies have shown that receptors such as HSP70 (N2a cell receptor), CLEC5A (C-type lectin receptor), TIM/TAM phosphatidylserine receptor, GRP78, D2 receptor, and v3 (a glycoprotein of the integrin family) may assist in the entry of JEV into the host cell via endocytosis.

• #13 Japanese Encephalitis (JE) Virus- An Overview

  https://microbenotes.com/japanese-encephalitis-je-virus/

  The portal of entry for the JE virus is through the bite of mosquito which contain virus. […] After the bite on skin the virus enter the Reticuloendothelial system (RES) and follows transient phase of viremia. […] After the transient viremia the virus invades the central nervous system. […] The virus enters the neuroparenchyma by crossing the capillary walls of brain and distributes itself in hypothalamus, hippocampus, substantia nigra and medulla oblongata regions of brain via vascular endothelial cells by the mechanism of endocytosis. […] The mechanism of endocytosis is either cholesterol or clathrin mediated pathway. […] Virus then replicates in neurons and matures in the neuronal secretory system. […] JE typically develops in patients after an incubation period of 5-15 days.

• #14 Molecular pathogenesis of Japanese encephalitis and possible therapeutic strategies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9162114/

  Japanese encephalitis virus (JEV), a single-stranded, enveloped RNA virus, is a health concern across Asian countries, associated with severe neurological disorders, especially in children. JEV requires a few host proteins for its entry and replication inside the mammalian host cell. The endoplasmic reticulum (ER) plays a significant role in JEV genome replication and assembly. During this process, the ER undergoes stress due to its remodelling and accumulation of viral particles and unfolded proteins, leading to an unfolded protein response (UPR). […] The SPs are incorporated into virus particles, whereas the NSPs participate in the formation of the replication complex (RC) and assembly complex (AC) and the replication of the viral genomic RNA. The newly assembled virus is in an immature form, and before leaving the host cell, it must undergo a maturation process. The maturation of JEV occurs due to consecutive reductions in pH in the successive components of host cell organelles.

• #15 Molecular pathogenesis of Japanese encephalitis and possible therapeutic strategies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9162114/

  Japanese encephalitis virus (JEV), a single-stranded, enveloped RNA virus, is a health concern across Asian countries, associated with severe neurological disorders, especially in children. JEV requires a few host proteins for its entry and replication inside the mammalian host cell. The endoplasmic reticulum (ER) plays a significant role in JEV genome replication and assembly. During this process, the ER undergoes stress due to its remodelling and accumulation of viral particles and unfolded proteins, leading to an unfolded protein response (UPR). […] The SPs are incorporated into virus particles, whereas the NSPs participate in the formation of the replication complex (RC) and assembly complex (AC) and the replication of the viral genomic RNA. The newly assembled virus is in an immature form, and before leaving the host cell, it must undergo a maturation process. The maturation of JEV occurs due to consecutive reductions in pH in the successive components of host cell organelles.

• #16

  https://link.springer.com/article/10.1007/s00705-022-05481-z

  Japanese encephalitis virus (JEV), a single-stranded, enveloped RNA virus, is a health concern across Asian countries, associated with severe neurological disorders, especially in children. […] JEV requires a few host proteins for its entry and replication inside the mammalian host cell. The endoplasmic reticulum (ER) plays a significant role in JEV genome replication and assembly. During this process, the ER undergoes stress due to its remodelling and accumulation of viral particles and unfolded proteins, leading to an unfolded protein response (UPR). […] We also highlight the role of JEV structural proteins (SPs) and non-structural proteins (NSPs) at various stages of the JEV life cycle that are involved in up- and downregulation of different host proteins and are potentially relevant for developing efficient therapeutic drugs.

• #17 Molecular Mechanism and Role of Japanese Encephalitis Virus Infection in Central Nervous System-Mediated Diseases

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9781168/

  The breaching of BBB is one of the most distinctive pathophysiologies of JEV. In addition to causing neuronal cell death, JEV propagation in astrocytes and microglia causes an upregulation of proinflammatory cytokines. JE is directly related to the inflammation and vasculitis of the brain and is associated with the invasion of the virus into the brain. JEV can infect BMECs, astrocytes, microglia, and pericytes, among other cell types found in the BBB. However, BMEC infection does not affect cell viability proposing that the BBB penetration by the JEV is not associated with JEV-mediated cell death. JEV infection actually suppresses tight junction protein expression and alters adherent localization, thus disrupting the tight junctions between the BMECs. […] JEV infection increases the production of proinflammatory cytokines, chemokines and signal transducers associated with the interferon (IFN-) pathways. Factors responsible for the analog of the JEV infection in the CNS are poorly understood.

• #18 Molecular Mechanism and Role of Japanese Encephalitis Virus Infection in Central Nervous System-Mediated Diseases

  https://www.mdpi.com/1999-4915/14/12/2686

  The breaching of BBB is one of the most distinctive pathophysiologies of JEV. In addition to causing neuronal cell death, JEV propagation in astrocytes and microglia causes an upregulation of proinflammatory cytokines. JE is directly related to the inflammation and vasculitis of the brain and is associated with the invasion of the virus into the brain. JEV can infect BMECs, astrocytes, microglia, and pericytes, among other cell types found in the BBB. However, BMEC infection does not affect cell viability proposing that the BBB penetration by the JEV is not associated with JEV-mediated cell death. JEV infection actually suppresses tight junction protein expression and alters adherent localization, thus disrupting the tight junctions between the BMECs. JEV infection-mediated release of IL-6, VEGF, MMP2, and MMP9 triggers astrocytes and pericytes, playing key roles in enhancing endothelial permeability. JEV infection also causes microglial activation resulting in the release of tumor necrosis factor α (TNF-α), IL-1β, IL-6, monocyte chemoattractant protein-1 (MCP-1), chemokine (C-C motif) ligand 5 (CCL5), CXC motif chemokine ligand 10 (CXCL10), and inducible nitric oxide synthase, which may be related to endothelial barrier damage. The breakdown of the BBB caused by JEV infection appears to be more of a side effect than a direct cause of viral proliferation in BMECs. Thus, elevated levels of inflammatory cytokines and chemokines, high viral titers in the brain, and fatalities caused by JE can all be connected.

• #19 Molecular Mechanism and Role of Japanese Encephalitis Virus Infection in Central Nervous System-Mediated Diseases

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9781168/

  The breaching of BBB is one of the most distinctive pathophysiologies of JEV. In addition to causing neuronal cell death, JEV propagation in astrocytes and microglia causes an upregulation of proinflammatory cytokines. JE is directly related to the inflammation and vasculitis of the brain and is associated with the invasion of the virus into the brain. JEV can infect BMECs, astrocytes, microglia, and pericytes, among other cell types found in the BBB. However, BMEC infection does not affect cell viability proposing that the BBB penetration by the JEV is not associated with JEV-mediated cell death. JEV infection actually suppresses tight junction protein expression and alters adherent localization, thus disrupting the tight junctions between the BMECs. […] JEV infection increases the production of proinflammatory cytokines, chemokines and signal transducers associated with the interferon (IFN-) pathways. Factors responsible for the analog of the JEV infection in the CNS are poorly understood.

• #20 Molecular Mechanism and Role of Japanese Encephalitis Virus Infection in Central Nervous System-Mediated Diseases

  https://www.mdpi.com/1999-4915/14/12/2686

  The breaching of BBB is one of the most distinctive pathophysiologies of JEV. In addition to causing neuronal cell death, JEV propagation in astrocytes and microglia causes an upregulation of proinflammatory cytokines. JE is directly related to the inflammation and vasculitis of the brain and is associated with the invasion of the virus into the brain. JEV can infect BMECs, astrocytes, microglia, and pericytes, among other cell types found in the BBB. However, BMEC infection does not affect cell viability proposing that the BBB penetration by the JEV is not associated with JEV-mediated cell death. JEV infection actually suppresses tight junction protein expression and alters adherent localization, thus disrupting the tight junctions between the BMECs. JEV infection-mediated release of IL-6, VEGF, MMP2, and MMP9 triggers astrocytes and pericytes, playing key roles in enhancing endothelial permeability. JEV infection also causes microglial activation resulting in the release of tumor necrosis factor α (TNF-α), IL-1β, IL-6, monocyte chemoattractant protein-1 (MCP-1), chemokine (C-C motif) ligand 5 (CCL5), CXC motif chemokine ligand 10 (CXCL10), and inducible nitric oxide synthase, which may be related to endothelial barrier damage. The breakdown of the BBB caused by JEV infection appears to be more of a side effect than a direct cause of viral proliferation in BMECs. Thus, elevated levels of inflammatory cytokines and chemokines, high viral titers in the brain, and fatalities caused by JE can all be connected.

• #21 Molecular Mechanism and Role of Japanese Encephalitis Virus Infection in Central Nervous System-Mediated Diseases

  https://www.mdpi.com/1999-4915/14/12/2686

  The breaching of BBB is one of the most distinctive pathophysiologies of JEV. In addition to causing neuronal cell death, JEV propagation in astrocytes and microglia causes an upregulation of proinflammatory cytokines. JE is directly related to the inflammation and vasculitis of the brain and is associated with the invasion of the virus into the brain. JEV can infect BMECs, astrocytes, microglia, and pericytes, among other cell types found in the BBB. However, BMEC infection does not affect cell viability proposing that the BBB penetration by the JEV is not associated with JEV-mediated cell death. JEV infection actually suppresses tight junction protein expression and alters adherent localization, thus disrupting the tight junctions between the BMECs. JEV infection-mediated release of IL-6, VEGF, MMP2, and MMP9 triggers astrocytes and pericytes, playing key roles in enhancing endothelial permeability. JEV infection also causes microglial activation resulting in the release of tumor necrosis factor α (TNF-α), IL-1β, IL-6, monocyte chemoattractant protein-1 (MCP-1), chemokine (C-C motif) ligand 5 (CCL5), CXC motif chemokine ligand 10 (CXCL10), and inducible nitric oxide synthase, which may be related to endothelial barrier damage. The breakdown of the BBB caused by JEV infection appears to be more of a side effect than a direct cause of viral proliferation in BMECs. Thus, elevated levels of inflammatory cytokines and chemokines, high viral titers in the brain, and fatalities caused by JE can all be connected.

• #22 Japanese encephalitis virus and its mechanisms of neuroinvasion | PLOS Pathogens

  https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1008260

  Japanese encephalitis virus (JEV) is a positive-sense single-stranded RNA virus of the Flavivirus genus that is spread by Culex mosquitos. It is maintained in an enzootic cycle in pigs and wild birds in which humans are dead-end hosts. Despite having effective vaccines, JEV is the leading cause of viral encephalitis in Asia. As a neuroinvasive virus, it can effectively cross the bloodbrain barrier (BBB) to cause acute encephalitis. Twenty-five percent to 30% of Japanese encephalitis (JE) cases are fatal, and 50% result in permanent neuropsychiatric complications. There are currently no treatments for JE, partly due to an incomplete understanding of the mechanisms promoting encephalitis. […] Neuroinvasive viruses use several mechanisms to access the CNS: (1) direct infection of endothelial cells and subsequent transcellular release of virus into the brain parenchyma, (2) infection of peripheral immune cells that enter the CNS in a Trojan Horse mechanism, (3) paracellular entry following breakdown of the BBB, (4) retrograde transport of virus from the peripheral nervous system (PNS) into the CNS, and (5) translocation from the blood to the cerebral spinal fluid (CSF).

• #23 Japanese encephalitis virus and its mechanisms of neuroinvasion | PLOS Pathogens

  https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1008260

  Japanese encephalitis virus (JEV) is a positive-sense single-stranded RNA virus of the Flavivirus genus that is spread by Culex mosquitos. It is maintained in an enzootic cycle in pigs and wild birds in which humans are dead-end hosts. Despite having effective vaccines, JEV is the leading cause of viral encephalitis in Asia. As a neuroinvasive virus, it can effectively cross the bloodbrain barrier (BBB) to cause acute encephalitis. Twenty-five percent to 30% of Japanese encephalitis (JE) cases are fatal, and 50% result in permanent neuropsychiatric complications. There are currently no treatments for JE, partly due to an incomplete understanding of the mechanisms promoting encephalitis. […] Neuroinvasive viruses use several mechanisms to access the CNS: (1) direct infection of endothelial cells and subsequent transcellular release of virus into the brain parenchyma, (2) infection of peripheral immune cells that enter the CNS in a Trojan Horse mechanism, (3) paracellular entry following breakdown of the BBB, (4) retrograde transport of virus from the peripheral nervous system (PNS) into the CNS, and (5) translocation from the blood to the cerebral spinal fluid (CSF).

• #24 Japanese encephalitis virus and its mechanisms of neuroinvasion | PLOS Pathogens

  https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1008260

  JEV has been visualized intracellularly in vesicles using electron microscopy and was suggested to undergo transcytosis across endothelial cells through pericytes into the brain of infected suckling mice. […] JEV gains entry into the brain through cleaved TJs is supported by reduced resistance across JEV-exposed cultured brain-endothelial-cell membranes in vitro and increased BBB leakiness and TJ protein breakdown in mouse models. […] JEV causes MC degranulation, which enhances JEV-induced breakdown of the BBB and augments infection in the brain. […] JEV infection amplifies BBB breakdown. Pericytes, which are situated within the basement membrane next to endothelial cells, aid in breakdown of the BBB through release of IL-6, which leads to ZO-1 degradation. […] JEV causes high morbidity and mortality in humans, leading to permanent neurological deficits, even in those who survive. Recent reports have advanced our understanding of the pathophysiological events that allow JEV to traverse the BBB and cause encephalitis. Although multiple routes of CNS entry are plausible, paracellular penetration of viruses resulting from protease and cytokine-driven breakdown of the BBB appears to be the dominant mechanism for JEV neuropenetration.

• #25 Japanese encephalitis virus and its mechanisms of neuroinvasion | PLOS Pathogens

  https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1008260

  JEV has been visualized intracellularly in vesicles using electron microscopy and was suggested to undergo transcytosis across endothelial cells through pericytes into the brain of infected suckling mice. […] JEV gains entry into the brain through cleaved TJs is supported by reduced resistance across JEV-exposed cultured brain-endothelial-cell membranes in vitro and increased BBB leakiness and TJ protein breakdown in mouse models. […] JEV causes MC degranulation, which enhances JEV-induced breakdown of the BBB and augments infection in the brain. […] JEV infection amplifies BBB breakdown. Pericytes, which are situated within the basement membrane next to endothelial cells, aid in breakdown of the BBB through release of IL-6, which leads to ZO-1 degradation. […] JEV causes high morbidity and mortality in humans, leading to permanent neurological deficits, even in those who survive. Recent reports have advanced our understanding of the pathophysiological events that allow JEV to traverse the BBB and cause encephalitis. Although multiple routes of CNS entry are plausible, paracellular penetration of viruses resulting from protease and cytokine-driven breakdown of the BBB appears to be the dominant mechanism for JEV neuropenetration.

• #26 Japanese encephalitis virus and its mechanisms of neuroinvasion | PLOS Pathogens

  https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1008260

  JEV has been visualized intracellularly in vesicles using electron microscopy and was suggested to undergo transcytosis across endothelial cells through pericytes into the brain of infected suckling mice. […] JEV gains entry into the brain through cleaved TJs is supported by reduced resistance across JEV-exposed cultured brain-endothelial-cell membranes in vitro and increased BBB leakiness and TJ protein breakdown in mouse models. […] JEV causes MC degranulation, which enhances JEV-induced breakdown of the BBB and augments infection in the brain. […] JEV infection amplifies BBB breakdown. Pericytes, which are situated within the basement membrane next to endothelial cells, aid in breakdown of the BBB through release of IL-6, which leads to ZO-1 degradation. […] JEV causes high morbidity and mortality in humans, leading to permanent neurological deficits, even in those who survive. Recent reports have advanced our understanding of the pathophysiological events that allow JEV to traverse the BBB and cause encephalitis. Although multiple routes of CNS entry are plausible, paracellular penetration of viruses resulting from protease and cytokine-driven breakdown of the BBB appears to be the dominant mechanism for JEV neuropenetration.

• #27 Japanese encephalitis virus and its mechanisms of neuroinvasion | PLOS Pathogens

  https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1008260

  JEV has been visualized intracellularly in vesicles using electron microscopy and was suggested to undergo transcytosis across endothelial cells through pericytes into the brain of infected suckling mice. […] JEV gains entry into the brain through cleaved TJs is supported by reduced resistance across JEV-exposed cultured brain-endothelial-cell membranes in vitro and increased BBB leakiness and TJ protein breakdown in mouse models. […] JEV causes MC degranulation, which enhances JEV-induced breakdown of the BBB and augments infection in the brain. […] JEV infection amplifies BBB breakdown. Pericytes, which are situated within the basement membrane next to endothelial cells, aid in breakdown of the BBB through release of IL-6, which leads to ZO-1 degradation. […] JEV causes high morbidity and mortality in humans, leading to permanent neurological deficits, even in those who survive. Recent reports have advanced our understanding of the pathophysiological events that allow JEV to traverse the BBB and cause encephalitis. Although multiple routes of CNS entry are plausible, paracellular penetration of viruses resulting from protease and cytokine-driven breakdown of the BBB appears to be the dominant mechanism for JEV neuropenetration.

• #28 Molecular pathogenesis of Japanese encephalitis and possible therapeutic strategies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9162114/

  Japanese encephalitis virus (JEV), a single-stranded, enveloped RNA virus, is a health concern across Asian countries, associated with severe neurological disorders, especially in children. JEV requires a few host proteins for its entry and replication inside the mammalian host cell. The endoplasmic reticulum (ER) plays a significant role in JEV genome replication and assembly. During this process, the ER undergoes stress due to its remodelling and accumulation of viral particles and unfolded proteins, leading to an unfolded protein response (UPR). […] The SPs are incorporated into virus particles, whereas the NSPs participate in the formation of the replication complex (RC) and assembly complex (AC) and the replication of the viral genomic RNA. The newly assembled virus is in an immature form, and before leaving the host cell, it must undergo a maturation process. The maturation of JEV occurs due to consecutive reductions in pH in the successive components of host cell organelles.

• #29 The mutation of Japanese encephalitis virus envelope protein residue 389 attenuates viral neuroinvasiveness | Virology Journal | Full Text

  https://virologyj.biomedcentral.com/articles/10.1186/s12985-024-02398-8

  The envelope (E) protein of the Japanese encephalitis virus (JEV) is a key protein for virus infection and adsorption of host cells, which determines the virulence of the virus and regulates the intensity of inflammatory response. […] This study demonstrated that the Asp to Gly, Ser, and His mutation of the E389 site, respectively, the replication ability of the viruses in cells was significantly reduced, and the viral neuroinvasiveness was attenuated to different degrees. […] Among them, the mutation at E389 site enhanced the E protein flexibility contributed to the attenuation of neuroinvasiveness. […] Our results indicate that the mechanism of attenuation of E389 aa mutation attenuates neuroinvasiveness is related to increased flexibility of the E protein. […] These results suggest that E389 residue is a potential site affecting JEV virulence, and the flexibility of the E protein of aa at this site plays an important role in the determination of neuroinvasiveness.

• #30 Near-atomic structure of Japanese encephalitis virus reveals critical determinants of virulence and stability | Nature Communications

  https://www.nature.com/articles/s41467-017-00024-6

  The structure reveals unusual holes between two monomers within a dimer, formed by cooperative shifts of the k-l hairpin, and i-j, E0-F0 and B0-C0 loops. […] These holes are surrounded by five encephalitis-specific motifs, which have been proposed to play a key role in the attachment of the encephalitic flaviviruses to their receptor(s). […] We have identified features that impart structural stability to the virus and thus play a role during the conformational changes of JEV. […] Notably, the Q264H mutation observed in an attenuated strain of JEV increases virus stability, hindering the series of conformational changes in the virion required for infection. […] Our studies on this attenuated strain of JEV further identify amino acids that impart neurovirulence in mice. […] The probable mechanism of attenuation of neurovirulence and its therapeutic implications are discussed.

• #31 Near-atomic structure of Japanese encephalitis virus reveals critical determinants of virulence and stability | Nature Communications

  https://www.nature.com/articles/s41467-017-00024-6

  Although several different flaviviruses may cause encephalitis, Japanese encephalitis virus is the most significant, being responsible for thousands of deaths each year in Asia. […] The structural and molecular basis of this encephalitis is not fully understood. […] Here, we report the cryo-electron microscopy structure of mature Japanese encephalitis virus at near-atomic resolution, which reveals an unusual hole on the surface, surrounded by five encephalitic-specific motifs implicated in receptor binding. […] Glu138 of E, which is highly conserved in encephalitic flaviviruses, maps onto one of these motifs and is essential for binding to neuroblastoma cells, with the E138K mutation abrogating the neurovirulence and neuroinvasiveness of Japanese encephalitis virus in mice. […] We also identify structural elements modulating viral stability, notably Gln264 of E, which, when replaced by His264 strengthens a hydrogen-bonding network, leading to a more stable virus.

• #32 Near-atomic structure of Japanese encephalitis virus reveals critical determinants of virulence and stability | Nature Communications

  https://www.nature.com/articles/s41467-017-00024-6

  The entry of flaviviruses into their target cells is mediated by the interaction of E with cell surface receptors. […] The JEV group may infect neurons by using receptor(s) distinct from those used by other flaviviruses. […] We have identified five encephalitis-specific motifs in the E protein surrounding the hole, which probably mediate attachment to neurons via electrostatic interactions. […] Residue Glu138 of the E protein, which is part of motif 3, is one of the points of greatest divergence (in terms of both sequence and structure) between the encephalitic and non-encephalitic viruses and we demonstrate that it plays an essential role in the attachment of the virus to neural cells. […] Furthermore, substitution of Glu138 by a lysine resulted in the increased susceptibility of virus infectivity to inhibition with GAGs, which is consistent with the correlation between GAG-binding affinity and neurovirulence.

• #33 Near-atomic structure of Japanese encephalitis virus reveals critical determinants of virulence and stability | Nature Communications

  https://www.nature.com/articles/s41467-017-00024-6

  Indeed, tissue culture adaptation not infrequently involves the gain of GAG-binding sites, relaxing the requirement for the usual cell receptor interaction. […] The best understood example of this structurally is foot-and-mouth disease virus and the simplest explanation of our results for JEV is that a key receptor for the encephalitic flaviviruses binds in the region we have identified, while mutation of Glu138 to a basic residue allows attachment of sulphated sugars of GAGs while simultaneously preventing cell entry via the usual receptor that confers neurovirulence. […] This is supported by the observation that the single E138K mutation is capable of completely blocking the lethal neurovirulence and neuroinvasiveness of JEV in mice.

• #34 The mutation of Japanese encephalitis virus envelope protein residue 389 attenuates viral neuroinvasiveness | Virology Journal | Full Text

  https://virologyj.biomedcentral.com/articles/10.1186/s12985-024-02398-8

  The acidity/alkalinity of the side chain of the E389 residues is associated with viral neuroinvasiveness. […] It suggested that the properties of residues 389 side chain plays an important role in JEV neuroinvasiveness. […] The mechanism of the loss of neuroinvasiveness of the viruses was investigated by examining the kinetics of viruses spread from the peripheral tissue of inoculation compared with that of the WT. […] The rapid clearance of the GAG-sensitive variant of JEV from the bloodstream prevented the sufficient magnitude and duration of viremia required for viral entry into the brain, which may account for the mechanism of attenuation of the neuroinvasiveness of the GAG-binding variant of JEV. […] Our data demonstrated that increased flexibility of the E protein of aa at E389 decreased JEV neuroinvasiveness, and that the mechanism of viral attenuation may also be related to the increase of GAG affinity.

• #35 The mutation of Japanese encephalitis virus envelope protein residue 389 attenuates viral neuroinvasiveness | Virology Journal | Full Text

  https://virologyj.biomedcentral.com/articles/10.1186/s12985-024-02398-8

  The acidity/alkalinity of the side chain of the E389 residues is associated with viral neuroinvasiveness. […] It suggested that the properties of residues 389 side chain plays an important role in JEV neuroinvasiveness. […] The mechanism of the loss of neuroinvasiveness of the viruses was investigated by examining the kinetics of viruses spread from the peripheral tissue of inoculation compared with that of the WT. […] The rapid clearance of the GAG-sensitive variant of JEV from the bloodstream prevented the sufficient magnitude and duration of viremia required for viral entry into the brain, which may account for the mechanism of attenuation of the neuroinvasiveness of the GAG-binding variant of JEV. […] Our data demonstrated that increased flexibility of the E protein of aa at E389 decreased JEV neuroinvasiveness, and that the mechanism of viral attenuation may also be related to the increase of GAG affinity.

• #36 Molecular pathogenesis of Japanese encephalitis and possible therapeutic strategies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9162114/

  Japanese encephalitis virus (JEV), a single-stranded, enveloped RNA virus, is a health concern across Asian countries, associated with severe neurological disorders, especially in children. JEV requires a few host proteins for its entry and replication inside the mammalian host cell. The endoplasmic reticulum (ER) plays a significant role in JEV genome replication and assembly. During this process, the ER undergoes stress due to its remodelling and accumulation of viral particles and unfolded proteins, leading to an unfolded protein response (UPR). […] The SPs are incorporated into virus particles, whereas the NSPs participate in the formation of the replication complex (RC) and assembly complex (AC) and the replication of the viral genomic RNA. The newly assembled virus is in an immature form, and before leaving the host cell, it must undergo a maturation process. The maturation of JEV occurs due to consecutive reductions in pH in the successive components of host cell organelles.

• #37 Molecular Mechanism and Role of Japanese Encephalitis Virus Infection in Central Nervous System-Mediated Diseases

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9781168/

  Apoptosis, triggered during the replication of JEV, leads to the death of neuronal and non-neuronal cells. […] Dimeric NS1 is a multifunctional glycoprotein that participates in JEV replications complex building and replication by interacting with other JEV non-structural proteins as well as many host proteins such as RPL18, RPL18a, vimentin, and hnRNP K. […] JEV relies on NS1 to survive inside the host cell via modulating the host immune response, and a single mutation in NS2A precludes NS1 production. […] JEV infection also triggers intracellular Ca2+ overload, which in turn correlates with abnormalities of mitochondrial membrane potential and protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and Janus tyrosine kinase (JAK)/signal transducer and activator of transcription 1 (STAT1) signaling pathways.

• #38 Molecular pathogenesis of Japanese encephalitis and possible therapeutic strategies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9162114/

  JEV requires NS1′ for its survival inside the host cell by modulating the host immune response, and it has been shown that a single mutation in NS2A prevents NS1′ formation. Therefore, as a regulator of NS1′, NS2A protein plays an essential role in JEV infection and pathogenesis. […] The NS2B-NS3 protease performs proteolytic cleavage specifically at dibasic amino acid motifs (K-R, R-R, R-K, or, rarely, Q-R) between NS2A and NS2B, between NS2B and NS3, NS3-NS4A, and between NS4B and NS5. […] The JEV NS3 protein has protease activity in its N-terminal domain and serves as binding site for the cofactor protein NS2B. NS3 also has helicase activity in its C-terminal domain that induces negative supercoiling (unwinding) of the dsRNA during viral RNA replication. […] The RdRp domain of NS5 contains three subdomains: palm, thumb, and finger. The palm subdomain contains conserved aspartic acid residues and forms the active site for the binding of RNA, metal ions, and nucleotides and is also involved in the transfer of phosphate groups.

• #39 Molecular Mechanism and Role of Japanese Encephalitis Virus Infection in Central Nervous System-Mediated Diseases

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9781168/

  Apoptosis, triggered during the replication of JEV, leads to the death of neuronal and non-neuronal cells. […] Dimeric NS1 is a multifunctional glycoprotein that participates in JEV replications complex building and replication by interacting with other JEV non-structural proteins as well as many host proteins such as RPL18, RPL18a, vimentin, and hnRNP K. […] JEV relies on NS1 to survive inside the host cell via modulating the host immune response, and a single mutation in NS2A precludes NS1 production. […] JEV infection also triggers intracellular Ca2+ overload, which in turn correlates with abnormalities of mitochondrial membrane potential and protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and Janus tyrosine kinase (JAK)/signal transducer and activator of transcription 1 (STAT1) signaling pathways.

• #40 Molecular Mechanism and Role of Japanese Encephalitis Virus Infection in Central Nervous System-Mediated Diseases

  https://www.mdpi.com/1999-4915/14/12/2686

  JEV relies on NS1′ to survive inside the host cell via modulating the host immune response, and a single mutation in NS2A precludes NS1′ production. As a result, as a regulator of NS1′, the NS2A protein is critical in JEV infection and pathogenesis. […] JEV infection also triggers intracellular Ca2+ overload, which in turn correlates with abnormalities of mitochondrial membrane potential and protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and Janus tyrosine kinase (JAK)/signal transducer and activator of transcription 1 (STAT1) signaling pathways.

• #41 Molecular Mechanism and Role of Japanese Encephalitis Virus Infection in Central Nervous System-Mediated Diseases

  https://www.mdpi.com/1999-4915/14/12/2686

  JEV relies on NS1′ to survive inside the host cell via modulating the host immune response, and a single mutation in NS2A precludes NS1′ production. As a result, as a regulator of NS1′, the NS2A protein is critical in JEV infection and pathogenesis. […] JEV infection also triggers intracellular Ca2+ overload, which in turn correlates with abnormalities of mitochondrial membrane potential and protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and Janus tyrosine kinase (JAK)/signal transducer and activator of transcription 1 (STAT1) signaling pathways.

• #42 Molecular pathogenesis of Japanese encephalitis and possible therapeutic strategies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9162114/

  JEV requires NS1′ for its survival inside the host cell by modulating the host immune response, and it has been shown that a single mutation in NS2A prevents NS1′ formation. Therefore, as a regulator of NS1′, NS2A protein plays an essential role in JEV infection and pathogenesis. […] The NS2B-NS3 protease performs proteolytic cleavage specifically at dibasic amino acid motifs (K-R, R-R, R-K, or, rarely, Q-R) between NS2A and NS2B, between NS2B and NS3, NS3-NS4A, and between NS4B and NS5. […] The JEV NS3 protein has protease activity in its N-terminal domain and serves as binding site for the cofactor protein NS2B. NS3 also has helicase activity in its C-terminal domain that induces negative supercoiling (unwinding) of the dsRNA during viral RNA replication. […] The RdRp domain of NS5 contains three subdomains: palm, thumb, and finger. The palm subdomain contains conserved aspartic acid residues and forms the active site for the binding of RNA, metal ions, and nucleotides and is also involved in the transfer of phosphate groups.

• #43 Molecular pathogenesis of Japanese encephalitis and possible therapeutic strategies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9162114/

  JEV requires NS1′ for its survival inside the host cell by modulating the host immune response, and it has been shown that a single mutation in NS2A prevents NS1′ formation. Therefore, as a regulator of NS1′, NS2A protein plays an essential role in JEV infection and pathogenesis. […] The NS2B-NS3 protease performs proteolytic cleavage specifically at dibasic amino acid motifs (K-R, R-R, R-K, or, rarely, Q-R) between NS2A and NS2B, between NS2B and NS3, NS3-NS4A, and between NS4B and NS5. […] The JEV NS3 protein has protease activity in its N-terminal domain and serves as binding site for the cofactor protein NS2B. NS3 also has helicase activity in its C-terminal domain that induces negative supercoiling (unwinding) of the dsRNA during viral RNA replication. […] The RdRp domain of NS5 contains three subdomains: palm, thumb, and finger. The palm subdomain contains conserved aspartic acid residues and forms the active site for the binding of RNA, metal ions, and nucleotides and is also involved in the transfer of phosphate groups.

• #44 Molecular pathogenesis of Japanese encephalitis and possible therapeutic strategies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9162114/

  The mechanisms by which JEV infects brain tissues and crosses the blood brain barrier as well as the consequences of these events have been reviewed. […] The JEV-NS5 protein has also been reported to affect the JAK-STAT pathway by inhibiting the phosphorylation of the STAT protein. […] The excessive accumulation of viral proteins in and around the ER lumen results in the modification of ER membrane. The modified ER membrane serves as a central site for genomic RNA replication, assembly, and maturation of the newly synthesised JEV viral particles. […] The NS5 protein is a crucial factor in JEV pathogenesis and therefore a potential drug target.

• #45 Molecular pathogenesis of Japanese encephalitis and possible therapeutic strategies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9162114/

  The mechanisms by which JEV infects brain tissues and crosses the blood brain barrier as well as the consequences of these events have been reviewed. […] The JEV-NS5 protein has also been reported to affect the JAK-STAT pathway by inhibiting the phosphorylation of the STAT protein. […] The excessive accumulation of viral proteins in and around the ER lumen results in the modification of ER membrane. The modified ER membrane serves as a central site for genomic RNA replication, assembly, and maturation of the newly synthesised JEV viral particles. […] The NS5 protein is a crucial factor in JEV pathogenesis and therefore a potential drug target.

• #46 Molecular pathogenesis of Japanese encephalitis and possible therapeutic strategies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9162114/

  JEV requires NS1′ for its survival inside the host cell by modulating the host immune response, and it has been shown that a single mutation in NS2A prevents NS1′ formation. Therefore, as a regulator of NS1′, NS2A protein plays an essential role in JEV infection and pathogenesis. […] The NS2B-NS3 protease performs proteolytic cleavage specifically at dibasic amino acid motifs (K-R, R-R, R-K, or, rarely, Q-R) between NS2A and NS2B, between NS2B and NS3, NS3-NS4A, and between NS4B and NS5. […] The JEV NS3 protein has protease activity in its N-terminal domain and serves as binding site for the cofactor protein NS2B. NS3 also has helicase activity in its C-terminal domain that induces negative supercoiling (unwinding) of the dsRNA during viral RNA replication. […] The RdRp domain of NS5 contains three subdomains: palm, thumb, and finger. The palm subdomain contains conserved aspartic acid residues and forms the active site for the binding of RNA, metal ions, and nucleotides and is also involved in the transfer of phosphate groups.

• #47 (PDF) Japanese Encephalitis: Pathogenesis, Prophylactics and Therapeutics

  https://www.academia.edu/308229/Japanese_Encephalitis_Pathogenesis_Prophylactics_and_Therapeutics

  Japanese Encephalitis (JE) is a significant vector-borne viral infection transmitted primarily by Culex mosquitoes, with a high prevalence in regions of Asia and the Pacific. […] The virus is transmitted to vertebrate hosts by mosquitoes belonging to the Culex sp. Pigs serve as amplification hosts and forms a critical link in the transmission cycle. […] In response to a JE virus attack, infected body cells start secretion of different cytokines and activate innate immune response. Virus starts neuronal invasion by entering into nerve cells and inflecting the central nervous system. It avoids exposure of body’s natural immunity and generates neurotrophic effects. Virus causes acute susceptibility to CNS and establishes encephalitis syndrome that results in very high fatality in children.

• #48 Molecular Mechanism and Role of Japanese Encephalitis Virus Infection in Central Nervous System-Mediated Diseases

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9781168/

  Apoptosis, triggered during the replication of JEV, leads to the death of neuronal and non-neuronal cells. […] Dimeric NS1 is a multifunctional glycoprotein that participates in JEV replications complex building and replication by interacting with other JEV non-structural proteins as well as many host proteins such as RPL18, RPL18a, vimentin, and hnRNP K. […] JEV relies on NS1 to survive inside the host cell via modulating the host immune response, and a single mutation in NS2A precludes NS1 production. […] JEV infection also triggers intracellular Ca2+ overload, which in turn correlates with abnormalities of mitochondrial membrane potential and protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and Janus tyrosine kinase (JAK)/signal transducer and activator of transcription 1 (STAT1) signaling pathways.

• #49 Molecular Mechanism and Role of Japanese Encephalitis Virus Infection in Central Nervous System-Mediated Diseases

  https://www.mdpi.com/1999-4915/14/12/2686

  JEV infection increases the production of proinflammatory cytokines, chemokines and signal transducers associated with the interferon γ (IFN-γ) pathways. Factors responsible for the analog of the JEV infection in the CNS are poorly understood. Mice affected with JEV show a high amount of cytokine and chemokine production in the brain. However, JEV immune splenocyte transfer could protect mice from extraneural JEV infection. Profiling of genes using high throughput screening (HTS) authorizes the identification of the critical genes that play an important role in the JEV infection and modulation of the pathways and also reveals the cellular and molecular pathways associated with this infection. […] Apoptosis, triggered during the replication of JEV, leads to the death of neuronal and non-neuronal cells. In human and mouse neuroblastoma cells, the energizing of tumor necrosis factor 1 (TNFR1) and signaling through tumor necrosis factor associated death domain (TRADD) prompt downstream apoptotic cascades during JEV infection.

• #50 Molecular Mechanism and Role of Japanese Encephalitis Virus Infection in Central Nervous System-Mediated Diseases

  https://www.mdpi.com/1999-4915/14/12/2686

  JEV infection increases the production of proinflammatory cytokines, chemokines and signal transducers associated with the interferon γ (IFN-γ) pathways. Factors responsible for the analog of the JEV infection in the CNS are poorly understood. Mice affected with JEV show a high amount of cytokine and chemokine production in the brain. However, JEV immune splenocyte transfer could protect mice from extraneural JEV infection. Profiling of genes using high throughput screening (HTS) authorizes the identification of the critical genes that play an important role in the JEV infection and modulation of the pathways and also reveals the cellular and molecular pathways associated with this infection. […] Apoptosis, triggered during the replication of JEV, leads to the death of neuronal and non-neuronal cells. In human and mouse neuroblastoma cells, the energizing of tumor necrosis factor 1 (TNFR1) and signaling through tumor necrosis factor associated death domain (TRADD) prompt downstream apoptotic cascades during JEV infection.

• #51 Pathogenesis and Host Immune Response during Japanese Encephalitis Virus Infection | IntechOpen

  https://www.intechopen.com/online-first/pathogenesis-and-host-immune-response-during-japanese-encephalitis-virus-infection

  The immunological processes that are required for clearance of virus are cell-type specific. However, in case JEV infection, the virus invade the host immune cells by cytolytic mechanism and hence, inhibiting the progression of NCP (neural progenitor cells pool). […] In response to the JEV infection, several mechanisms of innate immune response get activated. After getting infection, host cells starts producing various types of cytokines including type-1 IFN along with TNF- and IFN-. These cytokines induces inflammatory responses and hence, inhibits the viral replication. […] During JEV infection, viral clearance via immune cells is a multiple step process which involves both innate and adaptive immunity. […] Cytokines playing the lead in this mechanism is IFN- and IL-2 secreted by T-helper (Th) cells or T-cytotoxic (TC) cells.

• #52 Molecular Mechanism and Role of Japanese Encephalitis Virus Infection in Central Nervous System-Mediated Diseases

  https://www.mdpi.com/1999-4915/14/12/2686

  The breaching of BBB is one of the most distinctive pathophysiologies of JEV. In addition to causing neuronal cell death, JEV propagation in astrocytes and microglia causes an upregulation of proinflammatory cytokines. JE is directly related to the inflammation and vasculitis of the brain and is associated with the invasion of the virus into the brain. JEV can infect BMECs, astrocytes, microglia, and pericytes, among other cell types found in the BBB. However, BMEC infection does not affect cell viability proposing that the BBB penetration by the JEV is not associated with JEV-mediated cell death. JEV infection actually suppresses tight junction protein expression and alters adherent localization, thus disrupting the tight junctions between the BMECs. JEV infection-mediated release of IL-6, VEGF, MMP2, and MMP9 triggers astrocytes and pericytes, playing key roles in enhancing endothelial permeability. JEV infection also causes microglial activation resulting in the release of tumor necrosis factor α (TNF-α), IL-1β, IL-6, monocyte chemoattractant protein-1 (MCP-1), chemokine (C-C motif) ligand 5 (CCL5), CXC motif chemokine ligand 10 (CXCL10), and inducible nitric oxide synthase, which may be related to endothelial barrier damage. The breakdown of the BBB caused by JEV infection appears to be more of a side effect than a direct cause of viral proliferation in BMECs. Thus, elevated levels of inflammatory cytokines and chemokines, high viral titers in the brain, and fatalities caused by JE can all be connected.

• #53 Japanese encephalitis – Wikipedia

  https://en.wikipedia.org/wiki/Japanese_encephalitis

  Japanese encephalitis virus enters the brain through two ways and leads to infection of neurons and encephalitis. […] Increased microglial activation following Japanese encephalitis infection has been found to influence the outcome of viral pathogenesis. […] Activated microglia secrete cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-), which can cause toxic effects in the brain. […] In JE the tight regulation of microglial activation appears to be disturbed, resulting in an autotoxic loop of microglial activation that possibly leads to bystander neuronal damage. […] Recently, whole genome microarray research of neurons infected with the Japanese encephalitis virus has shown that neurons play an important role in their own defense against Japanese encephalitis infection. […] an improved understanding of the proinflammatory effects responsible for immune-mediated control of viral infection and neuronal injury during Japanese encephalitis infection is an essential step for developing strategies for limiting the severity of CNS disease.

• #54 Japanese encephalitis – Wikipedia

  https://en.wikipedia.org/wiki/Japanese_encephalitis

  Japanese encephalitis virus enters the brain through two ways and leads to infection of neurons and encephalitis. […] Increased microglial activation following Japanese encephalitis infection has been found to influence the outcome of viral pathogenesis. […] Activated microglia secrete cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-), which can cause toxic effects in the brain. […] In JE the tight regulation of microglial activation appears to be disturbed, resulting in an autotoxic loop of microglial activation that possibly leads to bystander neuronal damage. […] Recently, whole genome microarray research of neurons infected with the Japanese encephalitis virus has shown that neurons play an important role in their own defense against Japanese encephalitis infection. […] an improved understanding of the proinflammatory effects responsible for immune-mediated control of viral infection and neuronal injury during Japanese encephalitis infection is an essential step for developing strategies for limiting the severity of CNS disease.

• #55 Japanese encephalitis – Wikipedia

  https://en.wikipedia.org/wiki/Japanese_encephalitis

  Japanese encephalitis virus enters the brain through two ways and leads to infection of neurons and encephalitis. […] Increased microglial activation following Japanese encephalitis infection has been found to influence the outcome of viral pathogenesis. […] Activated microglia secrete cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-), which can cause toxic effects in the brain. […] In JE the tight regulation of microglial activation appears to be disturbed, resulting in an autotoxic loop of microglial activation that possibly leads to bystander neuronal damage. […] Recently, whole genome microarray research of neurons infected with the Japanese encephalitis virus has shown that neurons play an important role in their own defense against Japanese encephalitis infection. […] an improved understanding of the proinflammatory effects responsible for immune-mediated control of viral infection and neuronal injury during Japanese encephalitis infection is an essential step for developing strategies for limiting the severity of CNS disease.

• #56 Neuropathogenesis of Japanese Encephalitis in a Primate Model | PLOS Neglected Tropical Diseases

  https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0002980

  Despite the disease’s importance, little is known about the pathogenesis. During in vitro studies neuronal apoptosis was described, but its mechanisms and relevance for the disease are still unclear, in particular in relation to the inflammatory response that develops alongside direct viral cytopathology. […] Our study confirmed neurons as the main targets of JEV, as previously shown in fatal human cases. We also demonstrated viral antigen in microglial cells, mainly within microglial nodules surrounding infected neurons, suggesting virus uptake by phagocytosis. […] Apoptosis was shown by the TUNEL assay which has been used in the past to demonstrate apoptosis, although interpretation of the findings can be difficult in the presence of necrosis and autolytic changes; we therefore also confirmed apoptosis by staining for cleaved caspase-3. Apoptotic neurons were often surrounded by microglial cells (satellitosis and formation of microglial nodules) which indicated their impending phagocytosis.

• #57 Neuropathogenesis of Japanese Encephalitis in a Primate Model | PLOS Neglected Tropical Diseases

  https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0002980

  The occurrence of apoptosis in apparently uninfected neurons suggests that indirect mechanisms (bystander cell death) contribute to neuronal damage in JE, and indeed recent in vitro and in vivo murine studies demonstrated that microglial cells can induce neuronal apoptosis via the release of pro-inflammatory mediators. […] Our results indicate that in vivo this direct mechanism is probably less relevant and that pro-inflammatory factors are more important; this is also seen in other CNS conditions, such as experimental autoimmune encephalomyelitis (EAE) where microglial apoptosis is considered an important homeostatic mechanism to control microglial activation and proliferation. […] Our findings suggest new anti-inflammatory and anti-apoptotic therapeutic approaches may be useful in treating this debilitating disease.

• #58 Pathogenesis and Host Immune Response during Japanese Encephalitis Virus Infection | IntechOpen

  https://www.intechopen.com/chapters/77546

  One of the most characteristics pathogenesis of JEV is the breaching of BBB. Neuron being the most important target cell during JEV however, when the infection gets into CNS, along with the neuronal cells, astrocytes also gets infected, which is a constituent of BBB and an important part of CNS. Astrocytes are also considered to be helping in the transmission of JEV to the cerebrospinal fluid from peripheral tissues. The microglial cell that is considered to be the resident immune cells/macrophage of CNS is also infected by JEV. Microglial cells play a very significant role in CNS during the JEV infection via acting as a virus reservoir. Upon activation microglia produces proinflammatory cytokines like TNF-alpha and IL-6, which induce death of neuronal cell. […] The pathogenesis of JEV needs to be explored at dual phases in human which initiates at the peripheral tissues and then, involvement of central nervous system (CNS). JEV propagation occurs in neurons that results in neuronal cell death. Neuronal cell death occurs via two mechanism; direct and indirect neuronal killing. Direct killing involves the JEV propagation inside the neuronal cells that results in cell death and indirect killing involves aggressive and intense inflammatory responses leading to up-regulation of inflammatory cytokines and reactive oxygen species that causes death of neurons. […] In order to prevent the JEV pathogenesis, virus clearance from the peripheral nervous tissues during the initial phase of infection is crucial for designing effective therapy.

• #59 Pathogenesis and Host Immune Response during Japanese Encephalitis Virus Infection | IntechOpen

  https://www.intechopen.com/chapters/77546

  One of the most characteristics pathogenesis of JEV is the breaching of BBB. Neuron being the most important target cell during JEV however, when the infection gets into CNS, along with the neuronal cells, astrocytes also gets infected, which is a constituent of BBB and an important part of CNS. Astrocytes are also considered to be helping in the transmission of JEV to the cerebrospinal fluid from peripheral tissues. The microglial cell that is considered to be the resident immune cells/macrophage of CNS is also infected by JEV. Microglial cells play a very significant role in CNS during the JEV infection via acting as a virus reservoir. Upon activation microglia produces proinflammatory cytokines like TNF-alpha and IL-6, which induce death of neuronal cell. […] The pathogenesis of JEV needs to be explored at dual phases in human which initiates at the peripheral tissues and then, involvement of central nervous system (CNS). JEV propagation occurs in neurons that results in neuronal cell death. Neuronal cell death occurs via two mechanism; direct and indirect neuronal killing. Direct killing involves the JEV propagation inside the neuronal cells that results in cell death and indirect killing involves aggressive and intense inflammatory responses leading to up-regulation of inflammatory cytokines and reactive oxygen species that causes death of neurons. […] In order to prevent the JEV pathogenesis, virus clearance from the peripheral nervous tissues during the initial phase of infection is crucial for designing effective therapy.

• #60 Prevention, diagnosis, and management of Japanese encephalitis in chil | PHMT

  https://www.dovepress.com/prevention-diagnosis-and-management-of-japanese-encephalitis-in-childr-peer-reviewed-fulltext-article-PHMT

  Damage in flaviviral encephalitis appears to result both from direct virally mediated damage as well as host inflammatory response. Microglial cells undergo uncontrolled overactivation, releasing proinflammatory cytokines such as tumour necrosis factor alpha (TNFa), Monocyte Chemotactic Protein 1, interleukin 6 (IL-6), and RANTES (regulated upon activation, normal T cell expressed and secreted). […] This promotes massive leukocyte migration and infiltration in the brain. […] Besides neurons, astrocytes have also been shown to be infected with JEV. These cells release interferon inducible protein 10 (IP-10) which also contributes to leukocyte infiltration. […] There is also evidence that JEV suppresses the proliferation of neuronal progenitor cells which may result in neurological sequelae.

• #61 Molecular Mechanism and Role of Japanese Encephalitis Virus Infection in Central Nervous System-Mediated Diseases

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9781168/

  Apoptosis, triggered during the replication of JEV, leads to the death of neuronal and non-neuronal cells. […] Dimeric NS1 is a multifunctional glycoprotein that participates in JEV replications complex building and replication by interacting with other JEV non-structural proteins as well as many host proteins such as RPL18, RPL18a, vimentin, and hnRNP K. […] JEV relies on NS1 to survive inside the host cell via modulating the host immune response, and a single mutation in NS2A precludes NS1 production. […] JEV infection also triggers intracellular Ca2+ overload, which in turn correlates with abnormalities of mitochondrial membrane potential and protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and Janus tyrosine kinase (JAK)/signal transducer and activator of transcription 1 (STAT1) signaling pathways.

• #62 Molecular Mechanism and Role of Japanese Encephalitis Virus Infection in Central Nervous System-Mediated Diseases

  https://www.mdpi.com/1999-4915/14/12/2686

  JEV infection increases the production of proinflammatory cytokines, chemokines and signal transducers associated with the interferon γ (IFN-γ) pathways. Factors responsible for the analog of the JEV infection in the CNS are poorly understood. Mice affected with JEV show a high amount of cytokine and chemokine production in the brain. However, JEV immune splenocyte transfer could protect mice from extraneural JEV infection. Profiling of genes using high throughput screening (HTS) authorizes the identification of the critical genes that play an important role in the JEV infection and modulation of the pathways and also reveals the cellular and molecular pathways associated with this infection. […] Apoptosis, triggered during the replication of JEV, leads to the death of neuronal and non-neuronal cells. In human and mouse neuroblastoma cells, the energizing of tumor necrosis factor 1 (TNFR1) and signaling through tumor necrosis factor associated death domain (TRADD) prompt downstream apoptotic cascades during JEV infection.

• #63 Molecular Mechanism and Role of Japanese Encephalitis Virus Infection in Central Nervous System-Mediated Diseases

  https://www.mdpi.com/1999-4915/14/12/2686

  JEV infection increases the production of proinflammatory cytokines, chemokines and signal transducers associated with the interferon γ (IFN-γ) pathways. Factors responsible for the analog of the JEV infection in the CNS are poorly understood. Mice affected with JEV show a high amount of cytokine and chemokine production in the brain. However, JEV immune splenocyte transfer could protect mice from extraneural JEV infection. Profiling of genes using high throughput screening (HTS) authorizes the identification of the critical genes that play an important role in the JEV infection and modulation of the pathways and also reveals the cellular and molecular pathways associated with this infection. […] Apoptosis, triggered during the replication of JEV, leads to the death of neuronal and non-neuronal cells. In human and mouse neuroblastoma cells, the energizing of tumor necrosis factor 1 (TNFR1) and signaling through tumor necrosis factor associated death domain (TRADD) prompt downstream apoptotic cascades during JEV infection.

• #64 Molecular Mechanism and Role of Japanese Encephalitis Virus Infection in Central Nervous System-Mediated Diseases

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9781168/

  Apoptosis, triggered during the replication of JEV, leads to the death of neuronal and non-neuronal cells. […] Dimeric NS1 is a multifunctional glycoprotein that participates in JEV replications complex building and replication by interacting with other JEV non-structural proteins as well as many host proteins such as RPL18, RPL18a, vimentin, and hnRNP K. […] JEV relies on NS1 to survive inside the host cell via modulating the host immune response, and a single mutation in NS2A precludes NS1 production. […] JEV infection also triggers intracellular Ca2+ overload, which in turn correlates with abnormalities of mitochondrial membrane potential and protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and Janus tyrosine kinase (JAK)/signal transducer and activator of transcription 1 (STAT1) signaling pathways.

• #65 Molecular Mechanism and Role of Japanese Encephalitis Virus Infection in Central Nervous System-Mediated Diseases

  https://www.mdpi.com/1999-4915/14/12/2686

  JEV relies on NS1′ to survive inside the host cell via modulating the host immune response, and a single mutation in NS2A precludes NS1′ production. As a result, as a regulator of NS1′, the NS2A protein is critical in JEV infection and pathogenesis. […] JEV infection also triggers intracellular Ca2+ overload, which in turn correlates with abnormalities of mitochondrial membrane potential and protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and Janus tyrosine kinase (JAK)/signal transducer and activator of transcription 1 (STAT1) signaling pathways.

• #66 Prevention, diagnosis, and management of Japanese encephalitis in chil | PHMT

  https://www.dovepress.com/prevention-diagnosis-and-management-of-japanese-encephalitis-in-childr-peer-reviewed-fulltext-article-PHMT

  Damage in flaviviral encephalitis appears to result both from direct virally mediated damage as well as host inflammatory response. Microglial cells undergo uncontrolled overactivation, releasing proinflammatory cytokines such as tumour necrosis factor alpha (TNFa), Monocyte Chemotactic Protein 1, interleukin 6 (IL-6), and RANTES (regulated upon activation, normal T cell expressed and secreted). […] This promotes massive leukocyte migration and infiltration in the brain. […] Besides neurons, astrocytes have also been shown to be infected with JEV. These cells release interferon inducible protein 10 (IP-10) which also contributes to leukocyte infiltration. […] There is also evidence that JEV suppresses the proliferation of neuronal progenitor cells which may result in neurological sequelae.

• #67 Near-atomic structure of Japanese encephalitis virus reveals critical determinants of virulence and stability | Nature Communications

  https://www.nature.com/articles/s41467-017-00024-6

  These studies unveil determinants of neurovirulence and stability in Japanese encephalitis virus, opening up new avenues for therapeutic interventions against neurotropic flaviviruses. […] To cause encephalitis, the virus must gain entry to the central nervous system (CNS), a process known as viral neuroinvasiveness, and must replicate and cause damage within the CNS, a phenomenon known as neurovirulence. […] Over the past 20 years, many investigators have sought to discover the major genetic determinants critical for the virulence of JEV and identified a number of residues in the envelope (E) protein and some non-structural proteins, which significantly attenuate pathogenic JEV isolates. […] However, the molecular mechanisms underlying virulence are not clearly understood. […] We set out to clarify the mechanism for neurovirulence and to gain an understanding of the pathogenesis of encephalitic flaviviruses in the JE sero-group using a combination of structural analysis, cellular assays, reverse genetics, and animal studies of mouse models.

• #68 Near-atomic structure of Japanese encephalitis virus reveals critical determinants of virulence and stability | Nature Communications

  https://www.nature.com/articles/s41467-017-00024-6

  These studies unveil determinants of neurovirulence and stability in Japanese encephalitis virus, opening up new avenues for therapeutic interventions against neurotropic flaviviruses. […] To cause encephalitis, the virus must gain entry to the central nervous system (CNS), a process known as viral neuroinvasiveness, and must replicate and cause damage within the CNS, a phenomenon known as neurovirulence. […] Over the past 20 years, many investigators have sought to discover the major genetic determinants critical for the virulence of JEV and identified a number of residues in the envelope (E) protein and some non-structural proteins, which significantly attenuate pathogenic JEV isolates. […] However, the molecular mechanisms underlying virulence are not clearly understood. […] We set out to clarify the mechanism for neurovirulence and to gain an understanding of the pathogenesis of encephalitic flaviviruses in the JE sero-group using a combination of structural analysis, cellular assays, reverse genetics, and animal studies of mouse models.

• #69 Prevention, diagnosis, and management of Japanese encephalitis in chil | PHMT

  https://www.dovepress.com/prevention-diagnosis-and-management-of-japanese-encephalitis-in-childr-peer-reviewed-fulltext-article-PHMT

  The spectrum of clinical features ranges from an undifferentiated flu-like illness to severe meningoencephalitis. The JEV E protein plays a major role in virulence phenotype and even single amino acid substitutions of this may cause loss of neuroinvasiveness. […] Changes in receptor binding site and hinge region E 52 and E 270279 have been shown to result in loss of virulence. […] In addition, one more structural protein – the premembrane protein – contains glycosylation sites that showed protective potential. […] Among nonstructural proteins NS1 and NS3 are important ones that generate neurovirulence. […] After entering the body through a mosquito bite, the virus multiplies within host leukocytes (probably T lymphocytes), and is carried to the central nervous system. The JEV virions bind to the endothelial surface of the brain blood vessels and are internalized by endocytosis.

• #70 Prevention, diagnosis, and management of Japanese encephalitis in chil | PHMT

  https://www.dovepress.com/prevention-diagnosis-and-management-of-japanese-encephalitis-in-childr-peer-reviewed-fulltext-article-PHMT

  The spectrum of clinical features ranges from an undifferentiated flu-like illness to severe meningoencephalitis. The JEV E protein plays a major role in virulence phenotype and even single amino acid substitutions of this may cause loss of neuroinvasiveness. […] Changes in receptor binding site and hinge region E 52 and E 270279 have been shown to result in loss of virulence. […] In addition, one more structural protein – the premembrane protein – contains glycosylation sites that showed protective potential. […] Among nonstructural proteins NS1 and NS3 are important ones that generate neurovirulence. […] After entering the body through a mosquito bite, the virus multiplies within host leukocytes (probably T lymphocytes), and is carried to the central nervous system. The JEV virions bind to the endothelial surface of the brain blood vessels and are internalized by endocytosis.

• #71 Prevention, diagnosis, and management of Japanese encephalitis in chil | PHMT

  https://www.dovepress.com/prevention-diagnosis-and-management-of-japanese-encephalitis-in-childr-peer-reviewed-fulltext-article-PHMT

  The spectrum of clinical features ranges from an undifferentiated flu-like illness to severe meningoencephalitis. The JEV E protein plays a major role in virulence phenotype and even single amino acid substitutions of this may cause loss of neuroinvasiveness. […] Changes in receptor binding site and hinge region E 52 and E 270279 have been shown to result in loss of virulence. […] In addition, one more structural protein – the premembrane protein – contains glycosylation sites that showed protective potential. […] Among nonstructural proteins NS1 and NS3 are important ones that generate neurovirulence. […] After entering the body through a mosquito bite, the virus multiplies within host leukocytes (probably T lymphocytes), and is carried to the central nervous system. The JEV virions bind to the endothelial surface of the brain blood vessels and are internalized by endocytosis.

• #72 Near-atomic structure of Japanese encephalitis virus reveals critical determinants of virulence and stability | Nature Communications

  https://www.nature.com/articles/s41467-017-00024-6

  Although several different flaviviruses may cause encephalitis, Japanese encephalitis virus is the most significant, being responsible for thousands of deaths each year in Asia. […] The structural and molecular basis of this encephalitis is not fully understood. […] Here, we report the cryo-electron microscopy structure of mature Japanese encephalitis virus at near-atomic resolution, which reveals an unusual hole on the surface, surrounded by five encephalitic-specific motifs implicated in receptor binding. […] Glu138 of E, which is highly conserved in encephalitic flaviviruses, maps onto one of these motifs and is essential for binding to neuroblastoma cells, with the E138K mutation abrogating the neurovirulence and neuroinvasiveness of Japanese encephalitis virus in mice. […] We also identify structural elements modulating viral stability, notably Gln264 of E, which, when replaced by His264 strengthens a hydrogen-bonding network, leading to a more stable virus.

• #73 The mutation of Japanese encephalitis virus envelope protein residue 389 attenuates viral neuroinvasiveness | Virology Journal | Full Text

  https://virologyj.biomedcentral.com/articles/10.1186/s12985-024-02398-8

  The acidity/alkalinity of the side chain of the E389 residues is associated with viral neuroinvasiveness. […] It suggested that the properties of residues 389 side chain plays an important role in JEV neuroinvasiveness. […] The mechanism of the loss of neuroinvasiveness of the viruses was investigated by examining the kinetics of viruses spread from the peripheral tissue of inoculation compared with that of the WT. […] The rapid clearance of the GAG-sensitive variant of JEV from the bloodstream prevented the sufficient magnitude and duration of viremia required for viral entry into the brain, which may account for the mechanism of attenuation of the neuroinvasiveness of the GAG-binding variant of JEV. […] Our data demonstrated that increased flexibility of the E protein of aa at E389 decreased JEV neuroinvasiveness, and that the mechanism of viral attenuation may also be related to the increase of GAG affinity.

• #74 Japanese encephalitis | MedLink Neurology

  https://www.medlink.com/articles/japanese-encephalitis

  Japanese encephalitis is caused by the flavivirus Japanese encephalitis virus, which has a small (50 nm) lipoprotein envelope surrounding a nucleocapsid comprising of core protein and 11 KB single stranded RNA (3800 kD). […] In endemic areas, humans become infected with Japanese encephalitis virus after mosquito bites. The Japanese encephalitis virus multiplies locally and in regional nodes. After a phase of transient viremia, invasion of the central nervous system occurs via hematogenous spread. In the neurons, the virus replicates and matures in the neuronal secretory system, mainly the rough endoplasmic reticulum and Golgi apparatus, eventually destroying these structures. […] At autopsy, CNS findings in Japanese encephalitis reflect the inflammatory response to widespread neuronal infection with the virus. The thalamus, basal ganglia, midbrain, cerebellum, and anterior horns of the spinal cord are heavily affected, providing anatomical correlates for the tremor, dystonias, and flaccid paralysis that characterize the disease.

• #75 Japanese encephalitis | MedLink Neurology

  https://www.medlink.com/articles/japanese-encephalitis

  Invasion of neurons by the Japanese encephalitis virus is followed by perivascular cuffing, infiltration of inflammatory cells into the parenchyma, and phagocytosis of infected cells. […] Observations suggest that the increased microglial activation following Japanese encephalitis virus infection influences the outcome. It is likely that the increased microglial activation triggers bystander neuronal damage. Experimental studies suggest that neuronal apoptotic death and activation of microglial cells and astrocytes play a crucial role in the pathogenesis of Japanese encephalitis. The Japanese encephalitis virus induces neuronal apoptotic death and release of cytokines that initiate microglial activation and release of proinflammatory and apoptotic mediators with subsequent apoptotic death of both infected and uninfected neurons. […] Proinflammatory cytokine and chemokine levels in the CSF are associated with a bad outcome in patients with Japanese encephalitis.

• #76 Japanese encephalitis | MedLink Neurology

  https://www.medlink.com/articles/japanese-encephalitis

  Invasion of neurons by the Japanese encephalitis virus is followed by perivascular cuffing, infiltration of inflammatory cells into the parenchyma, and phagocytosis of infected cells. […] Observations suggest that the increased microglial activation following Japanese encephalitis virus infection influences the outcome. It is likely that the increased microglial activation triggers bystander neuronal damage. Experimental studies suggest that neuronal apoptotic death and activation of microglial cells and astrocytes play a crucial role in the pathogenesis of Japanese encephalitis. The Japanese encephalitis virus induces neuronal apoptotic death and release of cytokines that initiate microglial activation and release of proinflammatory and apoptotic mediators with subsequent apoptotic death of both infected and uninfected neurons. […] Proinflammatory cytokine and chemokine levels in the CSF are associated with a bad outcome in patients with Japanese encephalitis.

• #77 Japanese encephalitis | MedLink Neurology

  https://www.medlink.com/articles/japanese-encephalitis

  Invasion of neurons by the Japanese encephalitis virus is followed by perivascular cuffing, infiltration of inflammatory cells into the parenchyma, and phagocytosis of infected cells. […] Observations suggest that the increased microglial activation following Japanese encephalitis virus infection influences the outcome. It is likely that the increased microglial activation triggers bystander neuronal damage. Experimental studies suggest that neuronal apoptotic death and activation of microglial cells and astrocytes play a crucial role in the pathogenesis of Japanese encephalitis. The Japanese encephalitis virus induces neuronal apoptotic death and release of cytokines that initiate microglial activation and release of proinflammatory and apoptotic mediators with subsequent apoptotic death of both infected and uninfected neurons. […] Proinflammatory cytokine and chemokine levels in the CSF are associated with a bad outcome in patients with Japanese encephalitis.

• #78 Japanese encephalitis | MedLink Neurology

  https://www.medlink.com/articles/japanese-encephalitis

  Invasion of neurons by the Japanese encephalitis virus is followed by perivascular cuffing, infiltration of inflammatory cells into the parenchyma, and phagocytosis of infected cells. […] Observations suggest that the increased microglial activation following Japanese encephalitis virus infection influences the outcome. It is likely that the increased microglial activation triggers bystander neuronal damage. Experimental studies suggest that neuronal apoptotic death and activation of microglial cells and astrocytes play a crucial role in the pathogenesis of Japanese encephalitis. The Japanese encephalitis virus induces neuronal apoptotic death and release of cytokines that initiate microglial activation and release of proinflammatory and apoptotic mediators with subsequent apoptotic death of both infected and uninfected neurons. […] Proinflammatory cytokine and chemokine levels in the CSF are associated with a bad outcome in patients with Japanese encephalitis.

• #79 Japanese encephalitis – Wikipedia

  https://en.wikipedia.org/wiki/Japanese_encephalitis

  Japanese encephalitis virus enters the brain through two ways and leads to infection of neurons and encephalitis. […] Increased microglial activation following Japanese encephalitis infection has been found to influence the outcome of viral pathogenesis. […] Activated microglia secrete cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-), which can cause toxic effects in the brain. […] In JE the tight regulation of microglial activation appears to be disturbed, resulting in an autotoxic loop of microglial activation that possibly leads to bystander neuronal damage. […] Recently, whole genome microarray research of neurons infected with the Japanese encephalitis virus has shown that neurons play an important role in their own defense against Japanese encephalitis infection. […] an improved understanding of the proinflammatory effects responsible for immune-mediated control of viral infection and neuronal injury during Japanese encephalitis infection is an essential step for developing strategies for limiting the severity of CNS disease.

• #80 Japanese encephalitis – Wikipedia

  https://en.wikipedia.org/wiki/Japanese_encephalitis

  Japanese encephalitis virus enters the brain through two ways and leads to infection of neurons and encephalitis. […] Increased microglial activation following Japanese encephalitis infection has been found to influence the outcome of viral pathogenesis. […] Activated microglia secrete cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-), which can cause toxic effects in the brain. […] In JE the tight regulation of microglial activation appears to be disturbed, resulting in an autotoxic loop of microglial activation that possibly leads to bystander neuronal damage. […] Recently, whole genome microarray research of neurons infected with the Japanese encephalitis virus has shown that neurons play an important role in their own defense against Japanese encephalitis infection. […] an improved understanding of the proinflammatory effects responsible for immune-mediated control of viral infection and neuronal injury during Japanese encephalitis infection is an essential step for developing strategies for limiting the severity of CNS disease.

• #81 Pathogenesis and Host Immune Response during Japanese Encephalitis Virus Infection | IntechOpen

  https://www.intechopen.com/online-first/pathogenesis-and-host-immune-response-during-japanese-encephalitis-virus-infection

  The immunological processes that are required for clearance of virus are cell-type specific. However, in case JEV infection, the virus invade the host immune cells by cytolytic mechanism and hence, inhibiting the progression of NCP (neural progenitor cells pool). […] In response to the JEV infection, several mechanisms of innate immune response get activated. After getting infection, host cells starts producing various types of cytokines including type-1 IFN along with TNF- and IFN-. These cytokines induces inflammatory responses and hence, inhibits the viral replication. […] During JEV infection, viral clearance via immune cells is a multiple step process which involves both innate and adaptive immunity. […] Cytokines playing the lead in this mechanism is IFN- and IL-2 secreted by T-helper (Th) cells or T-cytotoxic (TC) cells.

• #82 Pathogenesis and Host Immune Response during Japanese Encephalitis Virus Infection | IntechOpen

  https://www.intechopen.com/online-first/pathogenesis-and-host-immune-response-during-japanese-encephalitis-virus-infection

  The immunological processes that are required for clearance of virus are cell-type specific. However, in case JEV infection, the virus invade the host immune cells by cytolytic mechanism and hence, inhibiting the progression of NCP (neural progenitor cells pool). […] In response to the JEV infection, several mechanisms of innate immune response get activated. After getting infection, host cells starts producing various types of cytokines including type-1 IFN along with TNF- and IFN-. These cytokines induces inflammatory responses and hence, inhibits the viral replication. […] During JEV infection, viral clearance via immune cells is a multiple step process which involves both innate and adaptive immunity. […] Cytokines playing the lead in this mechanism is IFN- and IL-2 secreted by T-helper (Th) cells or T-cytotoxic (TC) cells.

• #83 Pathogenesis and Host Immune Response during Japanese Encephalitis Virus Infection | IntechOpen

  https://www.intechopen.com/chapters/77546

  Japanese Encephalitis Virus (JEV) is a mosquito borne flavivirus infection. Once JEV makes its entry into blood, it infects monocytes wherein the viral replication peaks up without any cell death and results in production of TNF-. One of the most characteristics pathogenesis of JEV is the breaching of blood brain barrier (BBB). JEV propagation occurs in neurons that results in neuronal cell death as well as dissemination of virus into astrocytes and microglia leading to overexpression of proinflammatory cytokines. JEV infection results in host cells mediated secretion of various types of cytokines including type-1 IFN along with TNF- and IFN-. Molecule like nitrous oxide (NO) exhibits antiviral activities against JEV infection and helps in inhibiting the viral replication by blocking protein synthesis and viral RNA and also in virus infected cells clearance.

• #84 Pathogenesis and Host Immune Response during Japanese Encephalitis Virus Infection | IntechOpen

  https://www.intechopen.com/online-first/pathogenesis-and-host-immune-response-during-japanese-encephalitis-virus-infection

  Japanese Encephalitis Virus (JEV) is a mosquito borne flavivirus infection. Transmission of JEV starts with the infected mosquito bite where human dermis layer act as the primary site of infection. Once JEV makes its entry into blood, it infects monocytes wherein the viral replication peaks up without any cell death and results in production of TNF-. One of the most characteristics pathogenesis of JEV is the breaching of blood brain barrier (BBB). JEV propagation occurs in neurons that results in neuronal cell death as well as dissemination of virus into astrocytes and microglia leading to overexpression of proinflammatory cytokines. […] Molecule like nitrous oxide (NO) exhibits antiviral activities against JEV infection and helps in inhibiting the viral replication by blocking protein synthesis and viral RNA and also in virus infected cells clearance.

• #85 Pathogenesis and Host Immune Response during Japanese Encephalitis Virus Infection | IntechOpen

  https://www.intechopen.com/online-first/pathogenesis-and-host-immune-response-during-japanese-encephalitis-virus-infection

  The antibody binds to the epitopes necessary for the fusion of viral envelope with the plasma membrane and thus, blocking the penetration of virus molecules into the host cells. Furthermore, the antibody can also acts an opsonizing agent in order to facilitate the phagocytosis of viral particles, which is mediated by Fc or C3 receptor. […] Flaviviruses like JEV has taken the infection strategy into an advanced level by evading the detection machinery of the host-immune mechanism which is in responses to any viral infection to kill the virus- infected cells. JEV modulates the host machinery in dual ways that is, by virus-mediated damage and by host- immune responses. JEV alters or inhibit both the innate and adaptive immune responses of the host.

• #86 Pathogenesis and Host Immune Response during Japanese Encephalitis Virus Infection | IntechOpen

  https://www.intechopen.com/online-first/pathogenesis-and-host-immune-response-during-japanese-encephalitis-virus-infection

  JEV propagation occurs in neurons that results in neuronal cell death. Neuronal cell death occurs via two mechanism; direct and indirect neuronal killing. Direct killing involves the JEV propagation inside the neuronal cells that results in cell death and indirect killing involves aggressive and intense inflammatory responses leading to up-regulation of inflammatory cytokines and reactive oxygen species that causes death of neurons. […] In order to prevent the JEV pathogenesis, virus clearance from the peripheral nervous tissues during the initial phase of infection is crucial for designing effective therapy. […] The initial step focuses on the inhibition or on limiting the spread of virus to any new cells. In addition, already infected cells are then either eliminated or replication of JEV is suppressed permanently.

• #87 Pathogenesis and Host Immune Response during Japanese Encephalitis Virus Infection | IntechOpen

  https://www.intechopen.com/online-first/pathogenesis-and-host-immune-response-during-japanese-encephalitis-virus-infection

  The immunological processes that are required for clearance of virus are cell-type specific. However, in case JEV infection, the virus invade the host immune cells by cytolytic mechanism and hence, inhibiting the progression of NCP (neural progenitor cells pool). […] In response to the JEV infection, several mechanisms of innate immune response get activated. After getting infection, host cells starts producing various types of cytokines including type-1 IFN along with TNF- and IFN-. These cytokines induces inflammatory responses and hence, inhibits the viral replication. […] During JEV infection, viral clearance via immune cells is a multiple step process which involves both innate and adaptive immunity. […] Cytokines playing the lead in this mechanism is IFN- and IL-2 secreted by T-helper (Th) cells or T-cytotoxic (TC) cells.

• #88 Pathogenesis and Host Immune Response during Japanese Encephalitis Virus Infection | IntechOpen

  https://www.intechopen.com/online-first/pathogenesis-and-host-immune-response-during-japanese-encephalitis-virus-infection

  The antibody binds to the epitopes necessary for the fusion of viral envelope with the plasma membrane and thus, blocking the penetration of virus molecules into the host cells. Furthermore, the antibody can also acts an opsonizing agent in order to facilitate the phagocytosis of viral particles, which is mediated by Fc or C3 receptor. […] Flaviviruses like JEV has taken the infection strategy into an advanced level by evading the detection machinery of the host-immune mechanism which is in responses to any viral infection to kill the virus- infected cells. JEV modulates the host machinery in dual ways that is, by virus-mediated damage and by host- immune responses. JEV alters or inhibit both the innate and adaptive immune responses of the host.

• #89 Japanese B Encephalitis | Iowa State University

  https://vetmed.iastate.edu/vdpam/about/focus-areas/swine/swine-disease-manual/index-diseases/japanese-B-encephalitis

  Infected pigs remain viremic for several days. On the basis of research largely in other animals, the virus is believed to induce suppressor T-cells to produce a factor that suppresses humoral and cell mediated responses. This makes animals less resistant to infection. […] In porcine fetuses, the virus often causes the development of anomalies in the brain as well as encephalitis and degenerative neuronal changes. […] Transplacental infection in swine sometimes occurs. The effect of the virus depends on whether the fetuses are immunologically competent. When dams are infected between 40-60 days in gestation, fetuses often are killed and some are mummified. There may be no effect on fetuses if they are 85 or more days in gestation. Fetal deaths are believed to be caused by destruction of vital stem cells.

• #90 Molecular Mechanism and Role of Japanese Encephalitis Virus Infection in Central Nervous System-Mediated Diseases

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9781168/

  JEV is a flavivirus with a genome of about 11 kb ssRNA. Cell type-specific interactions of viral proteins with host machinery critically influence the nature of pathogenic outbursts. NS5 augments proinflammatory responses by disrupting host lipid metabolism, leading to elevated neurovirulence and neuroinvasiveness. […] Researchers have identified a few surface receptors mainly responsible for the entry of JEV into the nerve cells, namely C-type lectin domain family 5 member A (CLEC5A), Glucose regulated protein 78 (GRP78), Caveolin-1, D2-receptor (D2R), toll-like receptors (TLRs), and Src protein.

• #91 Prevention, diagnosis, and management of Japanese encephalitis in chil | PHMT

  https://www.dovepress.com/prevention-diagnosis-and-management-of-japanese-encephalitis-in-childr-peer-reviewed-fulltext-article-PHMT

  Damage in flaviviral encephalitis appears to result both from direct virally mediated damage as well as host inflammatory response. Microglial cells undergo uncontrolled overactivation, releasing proinflammatory cytokines such as tumour necrosis factor alpha (TNFa), Monocyte Chemotactic Protein 1, interleukin 6 (IL-6), and RANTES (regulated upon activation, normal T cell expressed and secreted). […] This promotes massive leukocyte migration and infiltration in the brain. […] Besides neurons, astrocytes have also been shown to be infected with JEV. These cells release interferon inducible protein 10 (IP-10) which also contributes to leukocyte infiltration. […] There is also evidence that JEV suppresses the proliferation of neuronal progenitor cells which may result in neurological sequelae.

• #92 Molecular pathogenesis of Japanese encephalitis and possible therapeutic strategies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9162114/

  The mechanisms by which JEV infects brain tissues and crosses the blood brain barrier as well as the consequences of these events have been reviewed. […] The JEV-NS5 protein has also been reported to affect the JAK-STAT pathway by inhibiting the phosphorylation of the STAT protein. […] The excessive accumulation of viral proteins in and around the ER lumen results in the modification of ER membrane. The modified ER membrane serves as a central site for genomic RNA replication, assembly, and maturation of the newly synthesised JEV viral particles. […] The NS5 protein is a crucial factor in JEV pathogenesis and therefore a potential drug target.

• #93 Emerging Japanese Encephalitis Virus Genotype V in Republic of Korea

  https://www.jmb.or.kr/journal/view.html?volume=32&number=8&spage=955

  Japanese encephalitis (JE) is a vaccine-preventable mosquito-borne disease caused by infection with the Japanese encephalitis virus (JEV). JEV has five genotypes, including genotype V (GV), which is considered ancestral to the other genotypes. Both GV Muar and GV XZ0934 are more pathogenic than other GI/GIII strains and are serologically distinct. However, because the ROKs GV strains have not been experimentally tested, their characteristics are not known. Characterization of the ROKs isolates is needed to enable development of effective GV strain-based vaccines to protect against GV infections. […] Japanese encephalitis virus (JEV), a member of the Flaviviridae family, is an enveloped positive-sense RNA virus that can cause viral meningoencephalitis. JEV infection is asymptomatic in more than 99% of cases; however, once JEV-infected patients develop encephalitis, the case-fatality rate can be up to 30%. Furthermore, 30%-50% of survivors have neurologic and psychiatric sequelae, making JE a particularly important public health problem if uncontrolled. Even though there are multiple effective vaccines against JEV, it remains a major pathogen due to its serious neuropathogenicity.

• #94 Emerging Japanese Encephalitis Virus Genotype V in Republic of Korea

  https://www.jmb.or.kr/journal/view.html?volume=32&number=8&spage=955

  Two earlier GV isolates, GV Muar and GV XZ0934, were tested for pathogenicity in mice. Mice infected with GV Muar had higher mortality rates than GI Mie/41-infected mice. When several chimeric viruses were generated between GV Muar and GI Mie/41, E and prM proteins of GV Muar were responsible for increased virulence. Specifically, histidine in position 123 of GV Muar E protein was most responsible for increased virulence. Also, GV XZ0934 was more neuropathogenic in a mouse model than GIII RP-9. […] The molecular basis for the pathogenesis of GV strains is still not well understood despite growing knowledge of its importance. Especially, virulence and other characteristics of ROKs GV isolates have not been tested. Although previous studies suggested that GV Muar and GV XZ0934 have greater virulence than other JEV genotype strains, it is possible that the ROKs GV strains have different pathogenicity and in vitro growth characteristics because of unique mutations. […] Overall, the epidemiologic data demonstrate a GI to GV shift in ROK but this observation has limitations because most of data are from mosquitoes. Only GV K15P38 has been isolated from human. Further genotyping of human isolates is required to define the clinical dominance of GV strain in ROK.

• #95 Emerging Japanese Encephalitis Virus Genotype V in Republic of Korea

  https://www.jmb.or.kr/journal/view.html?volume=32&number=8&spage=955

  Two earlier GV isolates, GV Muar and GV XZ0934, were tested for pathogenicity in mice. Mice infected with GV Muar had higher mortality rates than GI Mie/41-infected mice. When several chimeric viruses were generated between GV Muar and GI Mie/41, E and prM proteins of GV Muar were responsible for increased virulence. Specifically, histidine in position 123 of GV Muar E protein was most responsible for increased virulence. Also, GV XZ0934 was more neuropathogenic in a mouse model than GIII RP-9. […] The molecular basis for the pathogenesis of GV strains is still not well understood despite growing knowledge of its importance. Especially, virulence and other characteristics of ROKs GV isolates have not been tested. Although previous studies suggested that GV Muar and GV XZ0934 have greater virulence than other JEV genotype strains, it is possible that the ROKs GV strains have different pathogenicity and in vitro growth characteristics because of unique mutations. […] Overall, the epidemiologic data demonstrate a GI to GV shift in ROK but this observation has limitations because most of data are from mosquitoes. Only GV K15P38 has been isolated from human. Further genotyping of human isolates is required to define the clinical dominance of GV strain in ROK.

• #96 Emerging Japanese Encephalitis Virus Genotype V in Republic of Korea

  https://www.jmb.or.kr/journal/view.html?volume=32&number=8&spage=955

  Two earlier GV isolates, GV Muar and GV XZ0934, were tested for pathogenicity in mice. Mice infected with GV Muar had higher mortality rates than GI Mie/41-infected mice. When several chimeric viruses were generated between GV Muar and GI Mie/41, E and prM proteins of GV Muar were responsible for increased virulence. Specifically, histidine in position 123 of GV Muar E protein was most responsible for increased virulence. Also, GV XZ0934 was more neuropathogenic in a mouse model than GIII RP-9. […] The molecular basis for the pathogenesis of GV strains is still not well understood despite growing knowledge of its importance. Especially, virulence and other characteristics of ROKs GV isolates have not been tested. Although previous studies suggested that GV Muar and GV XZ0934 have greater virulence than other JEV genotype strains, it is possible that the ROKs GV strains have different pathogenicity and in vitro growth characteristics because of unique mutations. […] Overall, the epidemiologic data demonstrate a GI to GV shift in ROK but this observation has limitations because most of data are from mosquitoes. Only GV K15P38 has been isolated from human. Further genotyping of human isolates is required to define the clinical dominance of GV strain in ROK.

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