Materiały źródłowe

• #1 SARS-CoV-2 pathogenesis | Nature Reviews Microbiology

  https://www.nature.com/articles/s41579-022-00713-0

  The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a devastating pandemic. […] In this Review, we explore recent clinical and experimental advances regarding SARS-CoV-2 pathophysiology and discuss potential mechanisms behind SARS-CoV-2-associated acute respiratory distress syndrome (ARDS), specifically focusing on new insights obtained using novel technologies such as single-cell omics, organoid infection models and CRISPR screens. […] We describe how SARS-CoV-2 may infect the lower respiratory tract and cause alveolar damage as a result of dysfunctional immune responses. […] We discuss how this may lead to the induction of a leaky state of both the epithelium and the endothelium, promoting inflammation and coagulation, while an influx of immune cells leads to overexuberant inflammatory responses and immunopathology.

• #2 The pathogenesis of coronavirus-19 disease | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-022-00872-5

  Severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2) is the causal agent of coronavirus disease-2019 (COVID-19), a systemic illness characterized by variably severe pulmonary symptoms, cardiac conduction abnormalities, diarrhea, and gastrointestinal bleeding, as well as neurologic deficits, renal insufficiency, myalgias, endocrine abnormalities, and other perturbations that reflect widespread microvascular injury and a pro-inflammatory state. […] The mechanisms underlying the various manifestations of viral infection are incompletely understood but most data suggest that severe COVID-19 results from virus-driven perturbations in the immune system and resultant tissue injury. […] Aberrant interferon-related responses lead to alterations in cytokine elaboration that deplete resident immune cells while simultaneously recruiting hyperactive macrophages and functionally altered neutrophils, thereby tipping the balance from adaptive immunity to innate immunity.

• #3 COVID-19: Coronavirus replication, pathogenesis, and therapeutic strategies | Cleveland Clinic Journal of Medicine

  https://www.ccjm.org/content/87/6/321

  Human coronaviruses, along with influenza virus, human metapneumovirus, respiratory syncytial virus, and rhinovirus, are endemic and cause approximately 15% to 30% of annual respiratory tract infections. […] However, outbreaks of acute respiratory distress syndrome (ARDS) due to novel, highly pathogenic strains severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and now, SARS-CoV-2 have revealed the potency and danger of this expanding family of pathogens that have the capacity to kill many thousands of people around the world if not geographically contained. […] As in severe SARS and MERS disease, the mortality rate is disproportionately high in the elderly and patients with preexisting comorbidities such as heart disease, diabetes mellitus, hypertension, and renal disease. […] Higher morbidity in the elderly may partly be attributed to muted interferon antiviral responses as well as overall lower adaptive immunity, resulting, paradoxically, in longer courses of hyperactivity of the innate immune system (cytokine storm).

• #4 COVID-19: Coronavirus replication, pathogenesis, and therapeutic strategies | Cleveland Clinic Journal of Medicine

  https://www.ccjm.org/content/87/6/321

  Transmission from bats to intermediate hosts and then to humans, as well as from human to human, all involve viral adaptation, slight changes in viral sequence to improve fitness in the new host. […] SARS-CoV-2, the causative agent for the pandemic corona virus disease of 2019 (COVID-19) outbreak, was first found in Wuhan, China, and initial analysis of viral RNA obtained from patients hospitalized in late 2019 revealed it was 96% identical at the whole-genome level to a bat SARS-like coronavirus. […] The first two-thirds of the genome consists of 2 large overlapping open reading frames that encode 16 nonstructural proteins, including proteases, RNA-dependent RNA polymerase, RNA helicase, primase, and others, that form the viral replicase complex, a platform to propagate viral mRNAs. […] These nonstructural proteins are all potential targets for therapies, which would in theory work against all coronaviruses.

• #5

  https://link.springer.com/article/10.1007/s15010-020-01516-2

  The coronavirus outbreak emerged as a severe pandemic, claiming more than 0.8 million lives across the world and raised a major global health concern. […] The structural analysis of the spike protein and its disordered residues explains the mechanism of the viral transmission. […] The transmission rate of SARS-CoV-2 infection is higher compared to that of the closely related SARS-CoV infections. […] In SARS-CoV-2 infection, intrinsically disordered regions are observed at the interface of the spike protein and ACE2 receptor, providing a shape complementarity to the complex. […] The key residues of the spike protein have stronger binding affinity with ACE2. […] The overall history and mechanism of entry of SARS-CoV-2 along with structural study of spike-ACE2 complex provide insights to understand disease pathogenesis and development of vaccines and drugs.

• #6 SARS-CoV-2 pathogenesis | Nature Reviews Microbiology

  https://www.nature.com/articles/s41579-022-00713-0

  The main determinant of coronavirus tropism is the spike glycoprotein, which forms trimers on the surface of virions. […] The spike protein consists of two subunits: the S1 subunit, which binds to the host entry receptor angiotensin-converting enzyme 2 (ACE2), and the S2 subunit, which mediates membrane fusion. […] After binding to ACE2 on the target cell, the spike protein is cleaved by the transmembrane serine protease TMPRSS2 at the S2 site. […] The first cells targeted by SARS-CoV-2 during natural infection in humans are likely to be multiciliated cells in the nasopharynx or trachea, or sustentacular cells in the nasal olfactory mucosa. […] The main cytoplasmic PRR capable of detecting SARS-CoV-2 is thought to be MDA5, which recognizes long dsRNAs and initiates a signalling cascade to promote the transcription of type I and type III interferons.

• #7 Mechanisms of SARS-CoV-2 entry into cells | Nature Reviews Molecular Cell Biology

  https://www.nature.com/articles/s41580-021-00418-x

  The entry steps of the viral particles encompassing attachment to the host cell membrane and fusion are mediated by the S glycoprotein. S protein is assembled as a homotrimer and is inserted in multiple copies into the membrane of the virion giving it its crown-like appearance. […] SARS-CoV-2, like MERS-CoV, belongs to the first category: its S protein is cleaved by proprotein convertases such as furin in the virus-producer cells. Therefore, the S protein on the mature virion consists of two non-covalently associated subunits: the S1 subunit binds ACE2 and the S2 subunit anchors the S protein to the membrane. The S2 subunit also includes a fusion peptide and other machinery necessary to mediate membrane fusion upon infection of a new cell. […] Receptor engagement by viral entry glycoproteins, typically with other triggers, induces dramatic conformational changes in both subunits that bring the viral and cellular membranes together, ultimately creating a fusion pore that allows the viral genome to reach the cell cytoplasm. For SARS-CoV-2, one such trigger is the cleavage of an additional site internal to the S2 subunit, termed the S2 site. ACE2 engagement by the virus exposes the S2 site. S2 site cleavage by transmembrane protease, serine 2 (TMPRSS2) at the cell surface or by cathepsin L in the endosomal compartment following ACE2-mediated endocytosis releases the fusion peptide, initiating fusion pore formation.

• #8 Mechanisms of SARS-CoV-2 entry into cells | Nature Reviews Molecular Cell Biology

  https://www.nature.com/articles/s41580-021-00418-x

  The presence of a multibasic site (Arg-Arg-Ala-Arg) located at the S1S2 junction, which is cleaved by furin, distinguishes SARS-CoV-2 from SARS-CoV and all other known sarbecoviruses whose S protein is not cleaved by furin-like proteases during virus maturation in the infected cell. Cleavage of the S1S2 boundary is a prerequisite for the cleavage of the S2 site, and both cleavage events are essential to initiate the membrane-fusion process. […] After the S1S2 boundary is cleaved, the S2 site must also be cleaved to fully activate the fusion process either by TMPRSS2 on the cell surface or by cathepsins in the endosomes. TMPRSS2 is a type II transmembrane protein with serine protease activity whose major physiological role and substrate specificity are not well defined. […] Although SARS-CoV-2 prefers activation by TMPRSS2, cleavage of the S2 site can also be mediated by cathepsins, especially cathepsin L. If the target cells express insufficient TMPRSS2 or if a virus-ACE2 complex does not encounter TMPRSS2, ACE2-bound virus is internalized via clathrin-mediated endocytosis into the late endolysosome, where the S2 site is cleaved by cathepsins.

• #9

  https://link.springer.com/article/10.1007/s15010-020-01516-2

  The spike protein, which is responsible for the viral entry, has N-terminal and C-terminal domains, and two major subunits S1 and S2 are present in almost all coronaviruses. […] The spike protein is a clove-shaped trimer with three S1 heads and a trimeric S2 stalk. […] During viral infection, spike protein (~1300 amino acid residues) is cleaved by host proteases into receptor binding subunit S1 and membrane fusion subunit S2. […] The S1 subunit binds directly to the sugar receptors and ACE2 of the host cell surface, and the S2 subunit undergoes conformational changes and obtains post-fusion state. […] The viral entry to the host cells can be via: (1) the endocytic pathway and (2) non-endosomal pathway. […] The sequence similarity between SARS-CoV-2 and SARS-CoV spike protein explains the possibility of having the same receptor ACE2 in the host cell.

• #10 Epidemiology, transmission and pathogenesis of SARS-CoV-2

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9300483/

  The pathogenesis of COVID-19 involves the attachment, entry, and replication of the virus in the host cells. The gains entry into human cells through engagement of angiotensin-converting enzyme 2 receptor with its spike proteins. The overproduction of highly inflammatory cytokines results in a cytokine storm, leading to an increased risk of acute respiratory distress syndrome, coagulopathy, and multiorgan failure. […] Upon exposure of a healthy person to a SARS-CoV-2 infected person, viral particles reach the superficial epithelium of the nasal cavity. The viral spike glycoprotein of SARS-CoV-2 binds to the target cells by ACE2, present on the epithelial cells of the nasal cavity. The entry of the virus into the epithelial cells is facilitated by transmembrane serine protease 2 (TMPRSS2), which helps in the fusion of the membrane.

• #11 Mechanisms of SARS-CoV-2 entry into cells | Nature Reviews Molecular Cell Biology

  https://www.nature.com/articles/s41580-021-00418-x

  The entry steps of the viral particles encompassing attachment to the host cell membrane and fusion are mediated by the S glycoprotein. S protein is assembled as a homotrimer and is inserted in multiple copies into the membrane of the virion giving it its crown-like appearance. […] SARS-CoV-2, like MERS-CoV, belongs to the first category: its S protein is cleaved by proprotein convertases such as furin in the virus-producer cells. Therefore, the S protein on the mature virion consists of two non-covalently associated subunits: the S1 subunit binds ACE2 and the S2 subunit anchors the S protein to the membrane. The S2 subunit also includes a fusion peptide and other machinery necessary to mediate membrane fusion upon infection of a new cell. […] Receptor engagement by viral entry glycoproteins, typically with other triggers, induces dramatic conformational changes in both subunits that bring the viral and cellular membranes together, ultimately creating a fusion pore that allows the viral genome to reach the cell cytoplasm. For SARS-CoV-2, one such trigger is the cleavage of an additional site internal to the S2 subunit, termed the S2 site. ACE2 engagement by the virus exposes the S2 site. S2 site cleavage by transmembrane protease, serine 2 (TMPRSS2) at the cell surface or by cathepsin L in the endosomal compartment following ACE2-mediated endocytosis releases the fusion peptide, initiating fusion pore formation.

• #12

  https://link.springer.com/article/10.1007/s15010-020-01516-2

  The spike protein, which is responsible for the viral entry, has N-terminal and C-terminal domains, and two major subunits S1 and S2 are present in almost all coronaviruses. […] The spike protein is a clove-shaped trimer with three S1 heads and a trimeric S2 stalk. […] During viral infection, spike protein (~1300 amino acid residues) is cleaved by host proteases into receptor binding subunit S1 and membrane fusion subunit S2. […] The S1 subunit binds directly to the sugar receptors and ACE2 of the host cell surface, and the S2 subunit undergoes conformational changes and obtains post-fusion state. […] The viral entry to the host cells can be via: (1) the endocytic pathway and (2) non-endosomal pathway. […] The sequence similarity between SARS-CoV-2 and SARS-CoV spike protein explains the possibility of having the same receptor ACE2 in the host cell.

• #13 Mechanisms of SARS-CoV-2 entry into cells | Nature Reviews Molecular Cell Biology

  https://www.nature.com/articles/s41580-021-00418-x

  The presence of a multibasic site (Arg-Arg-Ala-Arg) located at the S1S2 junction, which is cleaved by furin, distinguishes SARS-CoV-2 from SARS-CoV and all other known sarbecoviruses whose S protein is not cleaved by furin-like proteases during virus maturation in the infected cell. Cleavage of the S1S2 boundary is a prerequisite for the cleavage of the S2 site, and both cleavage events are essential to initiate the membrane-fusion process. […] After the S1S2 boundary is cleaved, the S2 site must also be cleaved to fully activate the fusion process either by TMPRSS2 on the cell surface or by cathepsins in the endosomes. TMPRSS2 is a type II transmembrane protein with serine protease activity whose major physiological role and substrate specificity are not well defined. […] Although SARS-CoV-2 prefers activation by TMPRSS2, cleavage of the S2 site can also be mediated by cathepsins, especially cathepsin L. If the target cells express insufficient TMPRSS2 or if a virus-ACE2 complex does not encounter TMPRSS2, ACE2-bound virus is internalized via clathrin-mediated endocytosis into the late endolysosome, where the S2 site is cleaved by cathepsins.

• #14 Pathogenesis and Mechanisms of SARS-CoV-2 – ProQuest

  https://www.proquest.com/scholarly-journals/pathogenesis-mechanisms-sars-cov-2-infection/docview/2767188403/se-2

  Intracellularly, the viral genome is uncoated, released, and translated into various viral components. The replicase gene involves two open reading frames (ORFs) that encode the viral sections of the replication-transcription complex (RTC). Expression of the replicase gene and subsequent encoding of ORF1a and ORF1b leads to the production of replicase polyproteins, pp1a and pp1ab, respectively. The replicase polyproteins are cleaved by viral proteases into individual subunits of the RTC that are capable of associating with each other and host cell components to induce proviral changes in the environment. Nsp3, nsp4, and nsp6 have been shown to induce a change in membrane formation resulting in virus-induced double-membrane vesicles (DMVs), most likely derived from the endoplasmic reticulum (ER). The RTC participates in the replication and subsequent generation of a nested set of subgenomic RNA, which is translated into viral structural proteins (S, M, N, and E). The newly formed virus particles are assembled by exploiting the membranes and other elements of the ER and Golgi complex. Eventually, the mature virions are transported in vesicles and released from the cell via exocytosis into the extracellular compartments.

• #15 Pathogenesis and Mechanisms of SARS-CoV-2 – ProQuest

  https://www.proquest.com/scholarly-journals/pathogenesis-mechanisms-sars-cov-2-infection/docview/2767188403/se-2

  Intracellularly, the viral genome is uncoated, released, and translated into various viral components. The replicase gene involves two open reading frames (ORFs) that encode the viral sections of the replication-transcription complex (RTC). Expression of the replicase gene and subsequent encoding of ORF1a and ORF1b leads to the production of replicase polyproteins, pp1a and pp1ab, respectively. The replicase polyproteins are cleaved by viral proteases into individual subunits of the RTC that are capable of associating with each other and host cell components to induce proviral changes in the environment. Nsp3, nsp4, and nsp6 have been shown to induce a change in membrane formation resulting in virus-induced double-membrane vesicles (DMVs), most likely derived from the endoplasmic reticulum (ER). The RTC participates in the replication and subsequent generation of a nested set of subgenomic RNA, which is translated into viral structural proteins (S, M, N, and E). The newly formed virus particles are assembled by exploiting the membranes and other elements of the ER and Golgi complex. Eventually, the mature virions are transported in vesicles and released from the cell via exocytosis into the extracellular compartments.

• #16 Pathogenesis and Mechanisms of SARS-CoV-2 – ProQuest

  https://www.proquest.com/scholarly-journals/pathogenesis-mechanisms-sars-cov-2-infection/docview/2767188403/se-2

  Intracellularly, the viral genome is uncoated, released, and translated into various viral components. The replicase gene involves two open reading frames (ORFs) that encode the viral sections of the replication-transcription complex (RTC). Expression of the replicase gene and subsequent encoding of ORF1a and ORF1b leads to the production of replicase polyproteins, pp1a and pp1ab, respectively. The replicase polyproteins are cleaved by viral proteases into individual subunits of the RTC that are capable of associating with each other and host cell components to induce proviral changes in the environment. Nsp3, nsp4, and nsp6 have been shown to induce a change in membrane formation resulting in virus-induced double-membrane vesicles (DMVs), most likely derived from the endoplasmic reticulum (ER). The RTC participates in the replication and subsequent generation of a nested set of subgenomic RNA, which is translated into viral structural proteins (S, M, N, and E). The newly formed virus particles are assembled by exploiting the membranes and other elements of the ER and Golgi complex. Eventually, the mature virions are transported in vesicles and released from the cell via exocytosis into the extracellular compartments.

• #17 Pathogenesis and Mechanisms of SARS-CoV-2 – ProQuest

  https://www.proquest.com/scholarly-journals/pathogenesis-mechanisms-sars-cov-2-infection/docview/2767188403/se-2

  Viral modifications in the autophagic and extracellular vesicle pathways contribute to the overactivated and impaired immune responses that ultimately promote viral replication, the release of viral particles into the extracellular compartment, and the hypercoagulative states related to disease severity. Research shows that several cell types are affected by SARS-CoV-2 infection, with some having deleterious effects on disease severity and outcome, including epithelial, endothelial, and immune cells. Various immune and inflammatory changes induced by the virus contribute to endothelial cell damage and dysfunction in COVID-19 that may induce hypercoagulative states. In hypercoagulative states, there is an increased chance of developing lung thrombi and emboli that contribute to the respiratory distress and mortality encountered in COVID-19 patients.

• #18 SARS-CoV-2 pathogenesis | Nature Reviews Microbiology

  https://www.nature.com/articles/s41579-022-00713-0

  The main determinant of coronavirus tropism is the spike glycoprotein, which forms trimers on the surface of virions. […] The spike protein consists of two subunits: the S1 subunit, which binds to the host entry receptor angiotensin-converting enzyme 2 (ACE2), and the S2 subunit, which mediates membrane fusion. […] After binding to ACE2 on the target cell, the spike protein is cleaved by the transmembrane serine protease TMPRSS2 at the S2 site. […] The first cells targeted by SARS-CoV-2 during natural infection in humans are likely to be multiciliated cells in the nasopharynx or trachea, or sustentacular cells in the nasal olfactory mucosa. […] The main cytoplasmic PRR capable of detecting SARS-CoV-2 is thought to be MDA5, which recognizes long dsRNAs and initiates a signalling cascade to promote the transcription of type I and type III interferons.

• #19 COVID-19 Pathogenesis | Encyclopedia MDPI

  https://encyclopedia.pub/entry/14143

  The gateway for SARS-CoV-2 to target cells is the angiotensin-converting enzyme (ACE) 2 receptor, which is mostly expressed by epithelial cells of the lung, heart, blood vessels, kidneys, and intestines. […] The function of ACE is to split angiotensin I into angiotensin II, which binds and activates the type 1 angiotensin II receptor. This activation triggers a series of pathophysiological mechanisms that ultimately have vasoconstrictor, proinflammatory, and pro-oxidative effects. […] The ACE2 receptor has been implicated in the pathogenesis of COVID-19, especially with regards to its potential effects on the most vulnerable patients presenting with cardiovascular co-morbidities. COVID-19 does not have the same impact on all members of the population. An exponential increase in the severity of the disease as well as mortality, due to devastating thromboembolic complications, occurs in patients over the sixth decade of life with comorbidities such as cardiovascular disease and diabetes.

• #20 SARS-CoV-2 pathogenesis | Nature Reviews Microbiology

  https://www.nature.com/articles/s41579-022-00713-0

  The main determinant of coronavirus tropism is the spike glycoprotein, which forms trimers on the surface of virions. […] The spike protein consists of two subunits: the S1 subunit, which binds to the host entry receptor angiotensin-converting enzyme 2 (ACE2), and the S2 subunit, which mediates membrane fusion. […] After binding to ACE2 on the target cell, the spike protein is cleaved by the transmembrane serine protease TMPRSS2 at the S2 site. […] The first cells targeted by SARS-CoV-2 during natural infection in humans are likely to be multiciliated cells in the nasopharynx or trachea, or sustentacular cells in the nasal olfactory mucosa. […] The main cytoplasmic PRR capable of detecting SARS-CoV-2 is thought to be MDA5, which recognizes long dsRNAs and initiates a signalling cascade to promote the transcription of type I and type III interferons.

• #21 SARS-CoV-2 pathogenesis | Nature Reviews Microbiology

  https://www.nature.com/articles/s41579-022-00713-0

  If the virus is not cleared by innate or adaptive responses, it can spread to the lower respiratory tract by inhalation of virus particles from the upper respiratory tract or by gradual dissemination along the tracheobronchial tree. […] In the alveoli, SARS-CoV-2 has been shown to primarily infect alveolar type 2 (AT2) cells both in vivo and in vitro. […] The overall case fatality rate of COVID-19 is ~1%, and around 30% of people with COVID-19 require hospitalization, of which a considerable subset (~10-30%) require intensive care, putting great strain on health systems. […] Currently, no specific therapies for COVID-19 have been developed, highlighting our limited understanding of the pathogenesis of COVID-19. […] Histological examination of lung tissues of deceased individuals with COVID-19 on autopsy show that DAD is the predominant pattern of lung injury.

• #22 Pathogenesis of COVID‑19 Eurasian Journal of Pulmonology

  https://eurasianjpulmonol.com/article/55

  The coronavirus disease 2019 (COVID-19) is a very contagious infectious disease which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). […] Coronaviruses attach and enter to the host cells by means of the spikes on the cell membrane. The type 2 pneumocytes are the primary target of the virus. […] The aim of this report is to review the immunopathogenesis of COVID-19 in the light of current literature.

• #23 Pathology and Pathogenesis of SARS-CoV-2 Associated with Fatal Coronavirus Disease, United States – Volume 26, Number 9—September 2020 – Emerging Infectious Diseases journal – CDC

  https://wwwnc.cdc.gov/eid/article/26/9/20-2095_article

  Together, the histopathologic, IHC, and EM findings in this report provide insight into SARS-CoV-2 pathogenesis. […] The respiratory epithelium is one of the first cell types encountered by inhaled virus; SARS-CoV-2 antigens were detected by IHC in ciliated epithelial cells from 50% of these case-patients and up to 16 days after known symptom onset. […] Identification of SARS-CoV-2 cellular tropisms in the respiratory tract represents a crucial step forward in understanding the pathogenesis of SARS-CoV-2 infection and provides some insights relevant to the development of targeted therapeutic and preventive measures to combat COVID-19.

• #24 Pathology and Pathogenesis of SARS-CoV-2 Associated with Fatal Coronavirus Disease, United States

  https://stacks.cdc.gov/view/cdc/93027

  An ongoing pandemic of coronavirus disease (COVID-19) is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Characterization of the histopathology and cellular localization of SARS-CoV-2 in the tissues of patients with fatal COVID-19 is critical to further understand its pathogenesis and transmission and for public health prevention measures. […] We report clinicopathologic, immunohistochemical, and electron microscopic findings in tissues from 8 fatal laboratory-confirmed cases of SARS-CoV-2 infection in the United States. All cases except 1 were in residents of long-term care facilities. In these patients, SARS-CoV-2 infected epithelium of the upper and lower airways with diffuse alveolar damage as the predominant pulmonary pathology. SARS-CoV-2 was detectable by immunohistochemistry and electron microscopy in conducting airways, pneumocytes, alveolar macrophages, and a hilar lymph node but was not identified in other extrapulmonary tissues. […] Respiratory viral co-infections were identified in 3 cases; 3 cases had evidence of bacterial co-infection.

• #25 Epidemiology, transmission and pathogenesis of SARS-CoV-2

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9300483/

  Once the viral genome enters the host cell, its genes replicate, undergo transcription, and form new virions. After reaching the lower respiratory tract, the virus attaches to the alveolar epithelial cells through ACE2 receptors present on them. […] SARS-CoV-2 damages type-2 alveolar cells, which are essential for surfactant synthesis and repair of damaged tissues. Thus, there will be an increase in the surface tension, causing dyspnoea. In addition, the viral genome and proteins act as a pathogen-associated molecular pattern (PAMP) and stimulate the innate immune system. […] The common symptom in COVID-19 patients is hypoxia, if worsened, may lead to acute respiratory distress syndrome (ARDS). An unusual phenomenon seen in COVID patients is silent hypoxemia. […] The hematological manifestations in COVID-19 patients include both thrombotic and bleeding disorders. Disseminated-intravascular coagulation (DIC) has been noted in COVID-19 patients.

• #26 COVID-19 – Wikipedia

  https://en.wikipedia.org/wiki/COVID-19

  […] […] The virus can cause acute myocardial injury and chronic damage to the cardiovascular system. An acute cardiac injury was found in 12% of infected people admitted to the hospital in Wuhan, China, and is more frequent in severe disease. Rates of cardiovascular symptoms are high, owing to the systemic inflammatory response and immune system disorders during disease progression, but acute myocardial injuries may also be related to ACE2 receptors in the heart. ACE2 receptors are highly expressed in the heart and are involved in heart function. […] […] […] Another common cause of death is complications related to the kidneys. Early reports show that up to 30% of people hospitalised with COVID-19 both in China and in New York have experienced some injury to their kidneys, including some persons with no previous kidney problems.

• #27 Epidemiology, transmission and pathogenesis of SARS-CoV-2

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9300483/

  The frequent cardiovascular complications observed in COVID-19 patients are myocardial infarction, heart failure, venous-thromboembolic episodes, and palpitations. […] COVID-19 patients with preexisting renal diseases have a poor prognosis and have high mortality. […] The neurological manifestations in COVID-19 can be divided into two groups: central nervous system (CNS) manifestations and peripheral nervous system (PNS) manifestations. […] The SARS-CoV-2 infection also results in psychiatric manifestations like psychosis, posttraumatic stress disorder, and even suicide in some patients. […] Common dermatological manifestations observed in COVID-19 patients are maculopapular eruptions, acral areas of erythema with vesicles and pustules, urticarial lesions, vesicular eruptions, livedo or necrosis.

• #28 COVID-19 – Wikipedia

  https://en.wikipedia.org/wiki/COVID-19

  […] […] One common symptom, loss of smell, results from infection of the support cells of the olfactory epithelium, with subsequent damage to the olfactory neurons. The involvement of both the central and peripheral nervous system in COVID19 has been reported in many medical publications. It is clear that many people with COVID-19 exhibit neurological or mental health issues. The virus is not detected in the central nervous system (CNS) of the majority of people with COVID-19 who also have neurological issues. However, SARS-CoV-2 has been detected at low levels in the brains of those who have died from COVID19, but these results need to be confirmed. While virus has been detected in cerebrospinal fluid of autopsies, the exact mechanism by which it invades the CNS remains unclear and may first involve invasion of peripheral nerves given the low levels of ACE2 in the brain. The virus may also enter the bloodstream from the lungs and cross the bloodbrain barrier to gain access to the CNS, possibly within an infected white blood cell.

• #29 COVID-19 – Wikipedia

  https://en.wikipedia.org/wiki/COVID-19

  […] […] One common symptom, loss of smell, results from infection of the support cells of the olfactory epithelium, with subsequent damage to the olfactory neurons. The involvement of both the central and peripheral nervous system in COVID19 has been reported in many medical publications. It is clear that many people with COVID-19 exhibit neurological or mental health issues. The virus is not detected in the central nervous system (CNS) of the majority of people with COVID-19 who also have neurological issues. However, SARS-CoV-2 has been detected at low levels in the brains of those who have died from COVID19, but these results need to be confirmed. While virus has been detected in cerebrospinal fluid of autopsies, the exact mechanism by which it invades the CNS remains unclear and may first involve invasion of peripheral nerves given the low levels of ACE2 in the brain. The virus may also enter the bloodstream from the lungs and cross the bloodbrain barrier to gain access to the CNS, possibly within an infected white blood cell.

• #30 COVID-19 – Wikipedia

  https://en.wikipedia.org/wiki/COVID-19

  […] […] Research conducted when Alpha was the dominant variant has suggested COVID-19 may cause brain damage. Later research showed that all variants studied (including Omicron) killed brain cells, but the exact cells killed varied by variant. It is unknown if such damage is temporary or permanent. Observed individuals infected with COVID-19 (most with mild cases) experienced an additional 0.2% to 2% of brain tissue lost in regions of the brain connected to the sense of smell compared with uninfected individuals, and the overall effect on the brain was equivalent on average to at least one extra year of normal ageing; infected individuals also scored lower on several cognitive tests. All effects were more pronounced among older ages. […] […] […] The virus also affects gastrointestinal organs as ACE2 is abundantly expressed in the glandular cells of gastric, duodenal and rectal epithelium as well as endothelial cells and enterocytes of the small intestine.

• #31 Epidemiology, transmission and pathogenesis of SARS-CoV-2

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9300483/

  The frequent cardiovascular complications observed in COVID-19 patients are myocardial infarction, heart failure, venous-thromboembolic episodes, and palpitations. […] COVID-19 patients with preexisting renal diseases have a poor prognosis and have high mortality. […] The neurological manifestations in COVID-19 can be divided into two groups: central nervous system (CNS) manifestations and peripheral nervous system (PNS) manifestations. […] The SARS-CoV-2 infection also results in psychiatric manifestations like psychosis, posttraumatic stress disorder, and even suicide in some patients. […] Common dermatological manifestations observed in COVID-19 patients are maculopapular eruptions, acral areas of erythema with vesicles and pustules, urticarial lesions, vesicular eruptions, livedo or necrosis.

• #32 COVID-19 – Wikipedia

  https://en.wikipedia.org/wiki/COVID-19

  […] […] Research conducted when Alpha was the dominant variant has suggested COVID-19 may cause brain damage. Later research showed that all variants studied (including Omicron) killed brain cells, but the exact cells killed varied by variant. It is unknown if such damage is temporary or permanent. Observed individuals infected with COVID-19 (most with mild cases) experienced an additional 0.2% to 2% of brain tissue lost in regions of the brain connected to the sense of smell compared with uninfected individuals, and the overall effect on the brain was equivalent on average to at least one extra year of normal ageing; infected individuals also scored lower on several cognitive tests. All effects were more pronounced among older ages. […] […] […] The virus also affects gastrointestinal organs as ACE2 is abundantly expressed in the glandular cells of gastric, duodenal and rectal epithelium as well as endothelial cells and enterocytes of the small intestine.

• #33 Pathogenesis and Mechanisms of SARS-CoV-2 – ProQuest

  https://www.proquest.com/scholarly-journals/pathogenesis-mechanisms-sars-cov-2-infection/docview/2767188403/se-2

  The high expression of ACE2 in the alimentary tract makes the small and large bowels vulnerable to SARS-CoV-2 infection. Although fever, cough, and shortness of breath are the most common symptoms, around 17.6% of the patients present with gastrointestinal manifestations. Of the 17.6%, anorexia is the most common presentation in 26.8% of cases, followed by diarrhea (12.5%), nausea and vomiting (10.2%), and abdominal pain (9.2%). Furthermore, liver injury is observed in 15% to 53% of the cases. The positive detection of SARS-CoV-2 in stool constitutes evidence that the virus exists and replicates in the intestines of infected patients. More than half of the hospitalized patients with COVID-19 demonstrated positive stool samples, particularly those with diarrhea. SARS-CoV-2 viral shedding has been detected in the stool of COVID-19 patients and, as with most enteric viruses, it could be a potential fecal-oral transmission route. ACE2 is an important receptor on the cell membrane of host cells. It is widely distributed in various organs, including the nasopharynx, lung, esophagus, stomach, intestine, liver, and pancreas. Studies have shown that ACE2 is abundantly expressed in the gastrointestinal tract, particularly the colon, at approximately 100 times more than in the lung. The interaction between the virus’s transmembrane spike glycoprotein and the ACE2 receptor on enterocytes promotes the invasion of host brush border cells. The spike protein must be primed by TMPRSS2 which promotes endocytosis and facilitates the invasion of intestinal enterocytes by the SARS-CoV-2 virus.

• #34 Pathogenesis and Mechanisms of SARS-CoV-2 – ProQuest

  https://www.proquest.com/scholarly-journals/pathogenesis-mechanisms-sars-cov-2-infection/docview/2767188403/se-2

  The high expression of ACE2 in the alimentary tract makes the small and large bowels vulnerable to SARS-CoV-2 infection. Although fever, cough, and shortness of breath are the most common symptoms, around 17.6% of the patients present with gastrointestinal manifestations. Of the 17.6%, anorexia is the most common presentation in 26.8% of cases, followed by diarrhea (12.5%), nausea and vomiting (10.2%), and abdominal pain (9.2%). Furthermore, liver injury is observed in 15% to 53% of the cases. The positive detection of SARS-CoV-2 in stool constitutes evidence that the virus exists and replicates in the intestines of infected patients. More than half of the hospitalized patients with COVID-19 demonstrated positive stool samples, particularly those with diarrhea. SARS-CoV-2 viral shedding has been detected in the stool of COVID-19 patients and, as with most enteric viruses, it could be a potential fecal-oral transmission route. ACE2 is an important receptor on the cell membrane of host cells. It is widely distributed in various organs, including the nasopharynx, lung, esophagus, stomach, intestine, liver, and pancreas. Studies have shown that ACE2 is abundantly expressed in the gastrointestinal tract, particularly the colon, at approximately 100 times more than in the lung. The interaction between the virus’s transmembrane spike glycoprotein and the ACE2 receptor on enterocytes promotes the invasion of host brush border cells. The spike protein must be primed by TMPRSS2 which promotes endocytosis and facilitates the invasion of intestinal enterocytes by the SARS-CoV-2 virus.

• #35 COVID-19 – Wikipedia

  https://en.wikipedia.org/wiki/COVID-19

  […] […] The virus can cause acute myocardial injury and chronic damage to the cardiovascular system. An acute cardiac injury was found in 12% of infected people admitted to the hospital in Wuhan, China, and is more frequent in severe disease. Rates of cardiovascular symptoms are high, owing to the systemic inflammatory response and immune system disorders during disease progression, but acute myocardial injuries may also be related to ACE2 receptors in the heart. ACE2 receptors are highly expressed in the heart and are involved in heart function. […] […] […] Another common cause of death is complications related to the kidneys. Early reports show that up to 30% of people hospitalised with COVID-19 both in China and in New York have experienced some injury to their kidneys, including some persons with no previous kidney problems.

• #36 Epidemiology, transmission and pathogenesis of SARS-CoV-2

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9300483/

  ACE2 receptors and Ang 2 are widely expressed on all the components of the female reproductive system, including the ovary, uterus, and vagina. […] The most common gastrointestinal (GI) symptom observed in COVID-19 patients is diarrhea. Other symptoms include nausea, vomiting, abdominal discomfort, abdominal pain, and dysgeusia.

• #37 Epidemiology, transmission and pathogenesis of SARS-CoV-2

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9300483/

  The frequent cardiovascular complications observed in COVID-19 patients are myocardial infarction, heart failure, venous-thromboembolic episodes, and palpitations. […] COVID-19 patients with preexisting renal diseases have a poor prognosis and have high mortality. […] The neurological manifestations in COVID-19 can be divided into two groups: central nervous system (CNS) manifestations and peripheral nervous system (PNS) manifestations. […] The SARS-CoV-2 infection also results in psychiatric manifestations like psychosis, posttraumatic stress disorder, and even suicide in some patients. […] Common dermatological manifestations observed in COVID-19 patients are maculopapular eruptions, acral areas of erythema with vesicles and pustules, urticarial lesions, vesicular eruptions, livedo or necrosis.

• #38 SARS-CoV-2 pathogenesis | Nature Reviews Microbiology

  https://www.nature.com/articles/s41579-022-00713-0

  The main determinant of coronavirus tropism is the spike glycoprotein, which forms trimers on the surface of virions. […] The spike protein consists of two subunits: the S1 subunit, which binds to the host entry receptor angiotensin-converting enzyme 2 (ACE2), and the S2 subunit, which mediates membrane fusion. […] After binding to ACE2 on the target cell, the spike protein is cleaved by the transmembrane serine protease TMPRSS2 at the S2 site. […] The first cells targeted by SARS-CoV-2 during natural infection in humans are likely to be multiciliated cells in the nasopharynx or trachea, or sustentacular cells in the nasal olfactory mucosa. […] The main cytoplasmic PRR capable of detecting SARS-CoV-2 is thought to be MDA5, which recognizes long dsRNAs and initiates a signalling cascade to promote the transcription of type I and type III interferons.

• #39 Epidemiology, transmission and pathogenesis of SARS-CoV-2

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9300483/

  Once the viral genome enters the host cell, its genes replicate, undergo transcription, and form new virions. After reaching the lower respiratory tract, the virus attaches to the alveolar epithelial cells through ACE2 receptors present on them. […] SARS-CoV-2 damages type-2 alveolar cells, which are essential for surfactant synthesis and repair of damaged tissues. Thus, there will be an increase in the surface tension, causing dyspnoea. In addition, the viral genome and proteins act as a pathogen-associated molecular pattern (PAMP) and stimulate the innate immune system. […] The common symptom in COVID-19 patients is hypoxia, if worsened, may lead to acute respiratory distress syndrome (ARDS). An unusual phenomenon seen in COVID patients is silent hypoxemia. […] The hematological manifestations in COVID-19 patients include both thrombotic and bleeding disorders. Disseminated-intravascular coagulation (DIC) has been noted in COVID-19 patients.

• #40 COVID-19: Coronavirus replication, pathogenesis, and therapeutic strategies | Cleveland Clinic Journal of Medicine

  https://www.ccjm.org/content/87/6/321

  Features of coronavirus transmission, replication, and pathogenesis are determined by both the viral genome and the human host. […] Coronavirus spike proteins are key determinants for virus attachment and entry into target cells. The receptor for both SARS-CoV and SARS-CoV-2 is angiotensin-converting enzyme 2 (ACE2), a cell-surface enzyme contributing to control of blood pressure. […] The route or routes of infection thus depend on the proteases available in different cell types and the protease cleavage sites. […] Host proteases that cleave the S protein are also potential targets for antiviral drugs. A higher rate of SARS-CoV-2 infections compared with SARS-CoV infections may be at least partially explained by a higher affinity of spike protein for ACE2. […] During coevolution with their hosts, viruses have learned to counteract the interferon antiviral response. […] Like other human coronaviruses, SARS-CoV-2 can at least partly evade innate immunity to gain a foothold in humans, a critically important step in the infection cycle.

• #41 COVID-19 – Wikipedia

  https://en.wikipedia.org/wiki/COVID-19

  […] […] Although SARS-CoV-2 has a tropism for ACE2-expressing epithelial cells of the respiratory tract, people with severe COVID19 have symptoms of systemic hyperinflammation. Clinical laboratory findings of elevated IL2, IL6, IL7, as well as the following suggest an underlying immunopathology: Granulocyte-macrophage colony-stimulating factor (GMCSF), Interferon gamma-induced protein 10 (IP10), Monocyte chemoattractant protein 1 (MCP1), Macrophage inflammatory protein 1alpha (MIP1alpha), Tumour necrosis factor (TNF) indicative of cytokine release syndrome (CRS). […] […] […] Interferon alpha plays a complex, Janus-faced role in the pathogenesis of COVID-19. Although it promotes the elimination of virus-infected cells, it also upregulates the expression of ACE-2, thereby facilitating the SARS-Cov2 virus to enter cells and to replicate. A competition of negative feedback loops (via protective effects of interferon alpha) and positive feedback loops (via upregulation of ACE-2) is assumed to determine the fate of people with COVID-19.

• #42 COVID-19: Coronavirus replication, pathogenesis, and therapeutic strategies | Cleveland Clinic Journal of Medicine

  https://www.ccjm.org/content/87/6/321

  Severe disease is associated with lymphopenia and an uncontrolled systemic inflammatory response called a cytokine storm, which ultimately leads to multiple organ failure and death. […] Autopsy results reveal severe damage to endothelial tissue, vasculitis-like manifestations, and atrophy of secondary lymphoid tissues. […] The emergence of 3 highly pathogenic human coronaviruses within the past 20 years predicts that more of them will continue to come along. […] Clinical trials with drugs targeting viral proteins will reveal tolerance of the SARS-CoV-2 to selective pressure and guide in development of strategies that target host proteins required for replication.

• #43 The pathogenesis of coronavirus-19 disease | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-022-00872-5

  Severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2) is the causal agent of coronavirus disease-2019 (COVID-19), a systemic illness characterized by variably severe pulmonary symptoms, cardiac conduction abnormalities, diarrhea, and gastrointestinal bleeding, as well as neurologic deficits, renal insufficiency, myalgias, endocrine abnormalities, and other perturbations that reflect widespread microvascular injury and a pro-inflammatory state. […] The mechanisms underlying the various manifestations of viral infection are incompletely understood but most data suggest that severe COVID-19 results from virus-driven perturbations in the immune system and resultant tissue injury. […] Aberrant interferon-related responses lead to alterations in cytokine elaboration that deplete resident immune cells while simultaneously recruiting hyperactive macrophages and functionally altered neutrophils, thereby tipping the balance from adaptive immunity to innate immunity.

• #44 The pathogenesis of coronavirus-19 disease | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-022-00872-5

  Disproportionate activation of these macrophages and neutrophils further depletes normal activity of B-cells, T-cells, and natural killer (NK) cells. […] In addition, this pro-inflammatory state stimulates uncontrolled complement activation and development of neutrophil extracellular traps (NETS), both of which promote the coagulation cascade and induce a state of thrombo-inflammation. […] These perturbations have similar manifestations in multiple organ systems, which frequently show pathologic findings related to microvascular injury and thrombosis of large and small vessels. […] However, the pulmonary findings in patients with severe COVID-19 are generally more pronounced than those of other organs. […] Not only do they feature inflammatory thromboses and endothelial injury, but much of the parenchymal damage stems from failed maturation of alveolar pneumocytes, interactions between type 2 pneumocytes and non-resident macrophages, and a greater degree of NET formation. […] Understanding these mechanisms of injury is important to development of future therapies for patients with COVID-19, many of which will likely target specific components of the immune system, particularly NET induction, pro-inflammatory cytokines, and subpopulations of immune cells.

• #45 COVID-19 – Wikipedia

  https://en.wikipedia.org/wiki/COVID-19

  […] […] Although SARS-CoV-2 has a tropism for ACE2-expressing epithelial cells of the respiratory tract, people with severe COVID19 have symptoms of systemic hyperinflammation. Clinical laboratory findings of elevated IL2, IL6, IL7, as well as the following suggest an underlying immunopathology: Granulocyte-macrophage colony-stimulating factor (GMCSF), Interferon gamma-induced protein 10 (IP10), Monocyte chemoattractant protein 1 (MCP1), Macrophage inflammatory protein 1alpha (MIP1alpha), Tumour necrosis factor (TNF) indicative of cytokine release syndrome (CRS). […] […] […] Interferon alpha plays a complex, Janus-faced role in the pathogenesis of COVID-19. Although it promotes the elimination of virus-infected cells, it also upregulates the expression of ACE-2, thereby facilitating the SARS-Cov2 virus to enter cells and to replicate. A competition of negative feedback loops (via protective effects of interferon alpha) and positive feedback loops (via upregulation of ACE-2) is assumed to determine the fate of people with COVID-19.

• #46 COVID-19 infection: an overview on cytokine storm and related interventions | Virology Journal | Full Text

  https://virologyj.biomedcentral.com/articles/10.1186/s12985-022-01814-1

  As mentioned earlier, fatalities in the severe form of COVID-19 are strongly associated with CRS. Virtually all cells and tissues in the body can be influenced by cytokine storms. CRS is an acute and uncontrolled inflammatory response characterized by multi-organ dysfunction and diverse clinical manifestations such as fever. […] Importantly, ARDS seems to be the most serious complication of COVID-19, with a high mortality rate. In other words, ARDS is a consequence of CRS and leads to respiratory epithelium damage. […] Collectively, the uncontrolled release of cytokines may cause multi-organ damage in COVID-19 patients. […] Based on recent studies, it was strikingly shown that the level of inflammatory cytokines is increased in COVID-19. An overview of the literature indicates that IL-6, IL-2, IL-7, IL-10, granulocyte colony-stimulating factor (G-CSF), IFN-, inducible protein (IP)-10, TNF-, MCP-1, macrophage inflammatory protein (MIP)-1 play a crucial role in the pathogenesis of COVID-19.

• #47 COVID-19 – Wikipedia

  https://en.wikipedia.org/wiki/COVID-19

  […] […] Systemic inflammation results in vasodilation, allowing inflammatory lymphocytic and monocytic infiltration of the lung and the heart. In particular, pathogenic GM-CSF-secreting T cells were shown to correlate with the recruitment of inflammatory IL-6-secreting monocytes and severe lung pathology in people with COVID19. Lymphocytic infiltrates have also been reported at autopsy.

• #48 SARS-CoV-2 pathogenesis | Nature Reviews Microbiology

  https://www.nature.com/articles/s41579-022-00713-0

  Alveolar cell death or damage leads to a disruption of the alveolar epithelium, which sets off another key feature of the exudative phase of DAD seen in COVID-19: an imbalance between the activation of coagulation and the inhibition of fibrinolysis. […] The prothrombotic state seen in patients with COVID-19 is reminiscent of a process known as immunothrombosis, in which the immune and coagulation systems cooperate to block pathogens and limit their spread. […] What triggers the imbalance in the coagulation system in COVID-19 is currently poorly understood, but it may start with the disruption of the alveolar epithelium. […] Immune cells, attracted by cytokines and chemokines, also contribute to clotting. […] In patients with severe COVID-19, neutrophils express high levels of tissue factor and release NETs coated with tissue factor, which may further promote clotting.

• #49 SARS-CoV-2 pathogenesis | Nature Reviews Microbiology

  https://www.nature.com/articles/s41579-022-00713-0

  Alveolar cell death or damage leads to a disruption of the alveolar epithelium, which sets off another key feature of the exudative phase of DAD seen in COVID-19: an imbalance between the activation of coagulation and the inhibition of fibrinolysis. […] The prothrombotic state seen in patients with COVID-19 is reminiscent of a process known as immunothrombosis, in which the immune and coagulation systems cooperate to block pathogens and limit their spread. […] What triggers the imbalance in the coagulation system in COVID-19 is currently poorly understood, but it may start with the disruption of the alveolar epithelium. […] Immune cells, attracted by cytokines and chemokines, also contribute to clotting. […] In patients with severe COVID-19, neutrophils express high levels of tissue factor and release NETs coated with tissue factor, which may further promote clotting.

• #50 SARS-CoV-2 pathogenesis | Nature Reviews Microbiology

  https://www.nature.com/articles/s41579-022-00713-0

  Alveolar cell death or damage leads to a disruption of the alveolar epithelium, which sets off another key feature of the exudative phase of DAD seen in COVID-19: an imbalance between the activation of coagulation and the inhibition of fibrinolysis. […] The prothrombotic state seen in patients with COVID-19 is reminiscent of a process known as immunothrombosis, in which the immune and coagulation systems cooperate to block pathogens and limit their spread. […] What triggers the imbalance in the coagulation system in COVID-19 is currently poorly understood, but it may start with the disruption of the alveolar epithelium. […] Immune cells, attracted by cytokines and chemokines, also contribute to clotting. […] In patients with severe COVID-19, neutrophils express high levels of tissue factor and release NETs coated with tissue factor, which may further promote clotting.

• #51 Epidemiology, transmission and pathogenesis of SARS-CoV-2

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9300483/

  Once the viral genome enters the host cell, its genes replicate, undergo transcription, and form new virions. After reaching the lower respiratory tract, the virus attaches to the alveolar epithelial cells through ACE2 receptors present on them. […] SARS-CoV-2 damages type-2 alveolar cells, which are essential for surfactant synthesis and repair of damaged tissues. Thus, there will be an increase in the surface tension, causing dyspnoea. In addition, the viral genome and proteins act as a pathogen-associated molecular pattern (PAMP) and stimulate the innate immune system. […] The common symptom in COVID-19 patients is hypoxia, if worsened, may lead to acute respiratory distress syndrome (ARDS). An unusual phenomenon seen in COVID patients is silent hypoxemia. […] The hematological manifestations in COVID-19 patients include both thrombotic and bleeding disorders. Disseminated-intravascular coagulation (DIC) has been noted in COVID-19 patients.

• #52 SARS-CoV-2 pathogenesis | Nature Reviews Microbiology

  https://www.nature.com/articles/s41579-022-00713-0

  If the virus is not cleared by innate or adaptive responses, it can spread to the lower respiratory tract by inhalation of virus particles from the upper respiratory tract or by gradual dissemination along the tracheobronchial tree. […] In the alveoli, SARS-CoV-2 has been shown to primarily infect alveolar type 2 (AT2) cells both in vivo and in vitro. […] The overall case fatality rate of COVID-19 is ~1%, and around 30% of people with COVID-19 require hospitalization, of which a considerable subset (~10-30%) require intensive care, putting great strain on health systems. […] Currently, no specific therapies for COVID-19 have been developed, highlighting our limited understanding of the pathogenesis of COVID-19. […] Histological examination of lung tissues of deceased individuals with COVID-19 on autopsy show that DAD is the predominant pattern of lung injury.

• #53 SARS-CoV-2 pathogenesis | Nature Reviews Microbiology

  https://www.nature.com/articles/s41579-022-00713-0

  If the virus is not cleared by innate or adaptive responses, it can spread to the lower respiratory tract by inhalation of virus particles from the upper respiratory tract or by gradual dissemination along the tracheobronchial tree. […] In the alveoli, SARS-CoV-2 has been shown to primarily infect alveolar type 2 (AT2) cells both in vivo and in vitro. […] The overall case fatality rate of COVID-19 is ~1%, and around 30% of people with COVID-19 require hospitalization, of which a considerable subset (~10-30%) require intensive care, putting great strain on health systems. […] Currently, no specific therapies for COVID-19 have been developed, highlighting our limited understanding of the pathogenesis of COVID-19. […] Histological examination of lung tissues of deceased individuals with COVID-19 on autopsy show that DAD is the predominant pattern of lung injury.

• #54 The pathogenesis of coronavirus-19 disease | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-022-00872-5

  Disproportionate activation of these macrophages and neutrophils further depletes normal activity of B-cells, T-cells, and natural killer (NK) cells. […] In addition, this pro-inflammatory state stimulates uncontrolled complement activation and development of neutrophil extracellular traps (NETS), both of which promote the coagulation cascade and induce a state of thrombo-inflammation. […] These perturbations have similar manifestations in multiple organ systems, which frequently show pathologic findings related to microvascular injury and thrombosis of large and small vessels. […] However, the pulmonary findings in patients with severe COVID-19 are generally more pronounced than those of other organs. […] Not only do they feature inflammatory thromboses and endothelial injury, but much of the parenchymal damage stems from failed maturation of alveolar pneumocytes, interactions between type 2 pneumocytes and non-resident macrophages, and a greater degree of NET formation. […] Understanding these mechanisms of injury is important to development of future therapies for patients with COVID-19, many of which will likely target specific components of the immune system, particularly NET induction, pro-inflammatory cytokines, and subpopulations of immune cells.

• #55 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20210301/Cellular-maps-capture-COVID-19-pathogenesis-in-detail.aspx

  Researchers in the United States and Finland have used tissues from people who died from coronavirus disease 2019 (COVID-19) to generate detailed cellular maps of the pathogenetic processes that occur within affected organs during severe disease. […] Overall, our COVID-19 cell atlas is a foundational dataset to better understand the biological impact of SARS-CoV-2 infection across the human body and empowers the identification of new therapeutic interventions and prevention strategies, writes the team. […] Progression to ARDS is thought to involve a combination of increasing viral load, cytopathic effects, the translocation of SARS-CoV-2 to pulmonary tissue, and dysregulated immune responses. […] Evidence suggests that severe COVID-19 is characterized by a so-called cytokine storm of pro-inflammatory cytokines and an insufficient antiviral interferon response.

• #56 Epidemiology, transmission and pathogenesis of SARS-CoV-2

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9300483/

  Once the viral genome enters the host cell, its genes replicate, undergo transcription, and form new virions. After reaching the lower respiratory tract, the virus attaches to the alveolar epithelial cells through ACE2 receptors present on them. […] SARS-CoV-2 damages type-2 alveolar cells, which are essential for surfactant synthesis and repair of damaged tissues. Thus, there will be an increase in the surface tension, causing dyspnoea. In addition, the viral genome and proteins act as a pathogen-associated molecular pattern (PAMP) and stimulate the innate immune system. […] The common symptom in COVID-19 patients is hypoxia, if worsened, may lead to acute respiratory distress syndrome (ARDS). An unusual phenomenon seen in COVID patients is silent hypoxemia. […] The hematological manifestations in COVID-19 patients include both thrombotic and bleeding disorders. Disseminated-intravascular coagulation (DIC) has been noted in COVID-19 patients.

• #57 COVID-19 Pathogenesis | Encyclopedia MDPI

  https://encyclopedia.pub/entry/14143

  The ACE2 receptor facilitates SARS-CoV2 infection while the fundamental anti-inflammatory function, linked to RAS signaling, is reduced because it is compromised in patients who develop COVID-19. […] First, it is possible to hypothesize that in COVID-19 disease, the binding of SARS-CoV-2 to ACE2 receptors acutely exacerbates this proinflammatory background, predisposing these subpopulations to greater severity and mortality of COVID-19 disease.

• #58

  https://link.springer.com/article/10.1007/s12272-020-01301-7

  SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as the main receptor for host entry. […] SARS-CoV-2-induced ACE2 downregulation and its subsequent deficiency continuously block the conversion of angiotensin II into angiotensin 17. […] As a result, excessive angiotensin II is constantly available for AT1R hyperactivation. […] Therefore, ACE2 exerts protective functions in various RAS-based pathogenesis models involving acute and chronic inflammation. […] SARS-CoV-2-induced ACE2 deficiency can also antagonize the anti-inflammatory properties of angiotensin 17. […] Thus, SARS-CoV-2-induced ACE2 deficiency can also antagonize the anti-inflammatory properties of angiotensin 17. […] The cytokine storm induced by SARS-CoV-2 infection can be regarded as a self-elicited and suicidal systemic immunological reaction that can adversely affect every key organ in the body. […] COVID-19 pathogenesis stage-specific therapeutics should be selected to maximize patient recovery and survival.

• #59

  https://link.springer.com/article/10.1007/s12272-020-01301-7

  SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as the main receptor for host entry. […] SARS-CoV-2-induced ACE2 downregulation and its subsequent deficiency continuously block the conversion of angiotensin II into angiotensin 17. […] As a result, excessive angiotensin II is constantly available for AT1R hyperactivation. […] Therefore, ACE2 exerts protective functions in various RAS-based pathogenesis models involving acute and chronic inflammation. […] SARS-CoV-2-induced ACE2 deficiency can also antagonize the anti-inflammatory properties of angiotensin 17. […] Thus, SARS-CoV-2-induced ACE2 deficiency can also antagonize the anti-inflammatory properties of angiotensin 17. […] The cytokine storm induced by SARS-CoV-2 infection can be regarded as a self-elicited and suicidal systemic immunological reaction that can adversely affect every key organ in the body. […] COVID-19 pathogenesis stage-specific therapeutics should be selected to maximize patient recovery and survival.

• #60

  https://link.springer.com/article/10.1007/s12272-020-01301-7

  SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as the main receptor for host entry. […] SARS-CoV-2-induced ACE2 downregulation and its subsequent deficiency continuously block the conversion of angiotensin II into angiotensin 17. […] As a result, excessive angiotensin II is constantly available for AT1R hyperactivation. […] Therefore, ACE2 exerts protective functions in various RAS-based pathogenesis models involving acute and chronic inflammation. […] SARS-CoV-2-induced ACE2 deficiency can also antagonize the anti-inflammatory properties of angiotensin 17. […] Thus, SARS-CoV-2-induced ACE2 deficiency can also antagonize the anti-inflammatory properties of angiotensin 17. […] The cytokine storm induced by SARS-CoV-2 infection can be regarded as a self-elicited and suicidal systemic immunological reaction that can adversely affect every key organ in the body. […] COVID-19 pathogenesis stage-specific therapeutics should be selected to maximize patient recovery and survival.

• #61 COVID-19 infection: an overview on cytokine storm and related interventions | Virology Journal | Full Text

  https://virologyj.biomedcentral.com/articles/10.1186/s12985-022-01814-1

  Based on the IL-1-mediated inflammatory responses, it can be assumed that IL-1-mediated inflammation is responsible for the development of COVID-19 pathogenesis. […] It has been well established that the JAK-STAT pathway mediates the differentiation of Th17 cells. The signals from IL-6 and IL-23 can cause TH17 cell polarization from nave CD4+. […] Given the profound role of excessive TNF in the development, pathogenesis, and poor outcome of COVID-19, blockade of TNF offers a clinically effective intervention in this regard.

• #62 COVID-19 infection: an overview on cytokine storm and related interventions | Virology Journal | Full Text

  https://virologyj.biomedcentral.com/articles/10.1186/s12985-022-01814-1

  With this evidence, a great deal of attention has been paid to dampening signaling pathways of inflammatory cytokines aiming to reduce inflammatory responses and mortality in patients suffering from COVID-19. […] Given the essential role of IL-6 as a key driver in inflammatory status, and based on international guidelines, finding a suitable and efficient approach to inhibit IL-6 signaling is in demand. […] Recent evidence has implied the possible role of the inflammatory cytokines in the pathology of severe COVID-19. […] The role of IL-1 in the pathogenesis of COVID-19; hence, blocking IL-1-mediated activity is a reasonable therapeutic strategy. […] It is well documented that the release of IL-1 mainly depends on the expression of the (NLR family pyrin domain containing 3) NLRP3 inflammasome, which controls the maturation of IL-1.

• #63 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20210927/Review-of-COVID-19-clinical-and-viral-characteristics-pathogenesis-and-genetics.aspx

  The entry of SARS-CoV-2 inside the host cell depends on two factors including the recognition of the ACE2 receptor by the viral S protein and priming of the S protein by TMPRSS2. […] The cleavage results in the formation of separate S1 and S2 domains. […] The renin-angiotensinaldosterone system (RAAS) is a complex system that is responsible for maintaining the ACE/ACE2 balance in humans. Overactivation of RAAS can also be considered an important pathophysiological alteration that occurs during COVID-19. […] SARS-CoV-2 is known to activate both the acquired and innate immune responses. Furthermore, it causes cytokine storms, which are uncontrolled inflammatory responses brought about by high levels of circulating cytokines. […] The cytokine storm causes extensive tissue damage, body dysfunction, and ultimately death. Recent studies have found that out of all the inflammatory cytokines, interleukin 6 (IL-6) played a major role in the development of cytokine storms. Thus, it was concluded by many researchers that SARS-CoV-2 causes a chemokine, rather than a cytokine, storm. […] The FURIN gene encodes a protein convertase that causes cleavage of the SARS-CoV-2 S protein into two subunits, S1 and S2. The S2 subunit then causes fusion to occur between of the viral and host membranes, thus bringing about infection.

• #64 Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2022

  https://www.mdpi.com/1422-0067/24/22/16073

  Neutrophil extracellular traps (NETs) and oxidative stress at the center of infectious inflammation are thought to be useful for innate immune defense against pathogens. However, as shown by Hosseini et al., forced uncontrolled NET formation and lipid peroxidation in the lungs during COVID-19 infection can result in a critical complication of viral pneumonia, namely, the development of acute respiratory distress syndrome. […] Another paper in this Special Issue shows that the failure of antioxidant protection in severe COVID-19 cases may be associated with a polymorphism of the NFE2L2-KEAP1 genes, which are involved in cellular protection against oxidative stress. […] As demonstrated by these and other original and review papers in this Special Issue, effective treatment of COVID-19 requires a multi-stage, stage-specific approach to achieve a complete cure.

• #65 Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2022

  https://www.mdpi.com/1422-0067/24/22/16073

  Neutrophil extracellular traps (NETs) and oxidative stress at the center of infectious inflammation are thought to be useful for innate immune defense against pathogens. However, as shown by Hosseini et al., forced uncontrolled NET formation and lipid peroxidation in the lungs during COVID-19 infection can result in a critical complication of viral pneumonia, namely, the development of acute respiratory distress syndrome. […] Another paper in this Special Issue shows that the failure of antioxidant protection in severe COVID-19 cases may be associated with a polymorphism of the NFE2L2-KEAP1 genes, which are involved in cellular protection against oxidative stress. […] As demonstrated by these and other original and review papers in this Special Issue, effective treatment of COVID-19 requires a multi-stage, stage-specific approach to achieve a complete cure.

• #66 Fundamental Basis of COVID-19 Pathogenesis

  https://sciendo.com/article/10.2478/sjecr-2020-0029

  At the end of 2019, a new coronavirus infection occurred in the Peoples Republic of China with an epicentre in the city of Wuhan. […] The initial stage of COVID-19 infection is the penetration of SARS-CoV-2 into target cells that have angiotensin converting enzyme type II receptors. The virus enters the body through the respiratory tract and interacts primarily with toll-like receptors (TLRs). […] The events in SARS-Cov-2 induced infection follow the next scenario: epithelial cells via TLRs recognize and identify SARS-Cov-2, and after that the information is transmitted to the transcriptional NF-B, which causes expression of the corresponding genes. Activated in this way, the epithelial cells begin to synthesize various biologically active molecules. […] The results obtained on preclinical material indicate that ROS generation increases and the antioxidant protection decreases, which plays a major role in the pathogenesis of SARS-CoV, as well as in the progression and severity of this respiratory disease.

• #67 Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2022

  https://www.mdpi.com/1422-0067/24/22/16073

  Long COVID symptoms can last for up to 12 months or even longer. At the same time, they remain largely unexplained and under-researched, and it is unclear how long the symptoms of long COVID can persist. […] Chronic low-grade inflammation, in turn, leads to proinflammatory activation and the dysfunction of microglia and other brain cells with excessive cytokine release, causing various neuroinflammatory complications. […] Of particular concern among these complications is the pathogenetic association of long COVID with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) as well as its relationship with the onset and progression of neurodegenerative disorders. […] Persistent microvascular endotheliopathy associated with long COVID can potentially contribute to these and other serious complications. […] Clearly, the importance of studying long COVID will continue to grow for a long time to come.

• #68 Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2022

  https://www.mdpi.com/1422-0067/24/22/16073

  Long COVID symptoms can last for up to 12 months or even longer. At the same time, they remain largely unexplained and under-researched, and it is unclear how long the symptoms of long COVID can persist. […] Chronic low-grade inflammation, in turn, leads to proinflammatory activation and the dysfunction of microglia and other brain cells with excessive cytokine release, causing various neuroinflammatory complications. […] Of particular concern among these complications is the pathogenetic association of long COVID with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) as well as its relationship with the onset and progression of neurodegenerative disorders. […] Persistent microvascular endotheliopathy associated with long COVID can potentially contribute to these and other serious complications. […] Clearly, the importance of studying long COVID will continue to grow for a long time to come.

• #69 Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2022

  https://www.mdpi.com/1422-0067/24/22/16073

  Long COVID symptoms can last for up to 12 months or even longer. At the same time, they remain largely unexplained and under-researched, and it is unclear how long the symptoms of long COVID can persist. […] Chronic low-grade inflammation, in turn, leads to proinflammatory activation and the dysfunction of microglia and other brain cells with excessive cytokine release, causing various neuroinflammatory complications. […] Of particular concern among these complications is the pathogenetic association of long COVID with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) as well as its relationship with the onset and progression of neurodegenerative disorders. […] Persistent microvascular endotheliopathy associated with long COVID can potentially contribute to these and other serious complications. […] Clearly, the importance of studying long COVID will continue to grow for a long time to come.

• #70 Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2021

  https://www.mdpi.com/1422-0067/23/22/14210

  Metabolic dysfunctions are often associated with aging processes and endocrine dysfunctions, including as a result of decreased testosterone levels in the blood. Meanwhile, there is a less studied problem of virus-induced changes in metabolic pathways known as metabolic reprogramming. Studies on COVID-19 have found significant changes in metabolism that led to the conclusion that COVID-19 is a metabolic disease. […] A separate problem is the possible impact of COVID-19 on the course of chronic socially significant diseases. In particular, immune suppression caused by the SARS-CoV-2 can cause difficulties in the diagnosis and treatment of tuberculosis. […] The alarming phenomenon is what the literature refers to as long COVID, long-haul COVID-19, post-COVID syndrome, chronic COVID syndrome, or post-acute sequelae of SARS-COV-2 infection (PASC). Of particular concern are the numerous overlaps in the clinical manifestations of the chronic consequences of COVID-19 (>6 months) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which is a socially significant problem of the modern world. At the same time, the pathogenesis of long COVID is diverse and far from being clear throughout, including the effect on the nervous, vascular and other systems not only of SARS-CoV-2 itself, but also abnormal reactions of the organism to viral invasion.

• #71 Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2022

  https://www.mdpi.com/1422-0067/24/22/16073

  Long COVID symptoms can last for up to 12 months or even longer. At the same time, they remain largely unexplained and under-researched, and it is unclear how long the symptoms of long COVID can persist. […] Chronic low-grade inflammation, in turn, leads to proinflammatory activation and the dysfunction of microglia and other brain cells with excessive cytokine release, causing various neuroinflammatory complications. […] Of particular concern among these complications is the pathogenetic association of long COVID with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) as well as its relationship with the onset and progression of neurodegenerative disorders. […] Persistent microvascular endotheliopathy associated with long COVID can potentially contribute to these and other serious complications. […] Clearly, the importance of studying long COVID will continue to grow for a long time to come.

• #72 The pathogenesis of coronavirus-19 disease | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-022-00872-5

  Disproportionate activation of these macrophages and neutrophils further depletes normal activity of B-cells, T-cells, and natural killer (NK) cells. […] In addition, this pro-inflammatory state stimulates uncontrolled complement activation and development of neutrophil extracellular traps (NETS), both of which promote the coagulation cascade and induce a state of thrombo-inflammation. […] These perturbations have similar manifestations in multiple organ systems, which frequently show pathologic findings related to microvascular injury and thrombosis of large and small vessels. […] However, the pulmonary findings in patients with severe COVID-19 are generally more pronounced than those of other organs. […] Not only do they feature inflammatory thromboses and endothelial injury, but much of the parenchymal damage stems from failed maturation of alveolar pneumocytes, interactions between type 2 pneumocytes and non-resident macrophages, and a greater degree of NET formation. […] Understanding these mechanisms of injury is important to development of future therapies for patients with COVID-19, many of which will likely target specific components of the immune system, particularly NET induction, pro-inflammatory cytokines, and subpopulations of immune cells.

• #73

  https://link.springer.com/article/10.1007/s12272-020-01301-7

  SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as the main receptor for host entry. […] SARS-CoV-2-induced ACE2 downregulation and its subsequent deficiency continuously block the conversion of angiotensin II into angiotensin 17. […] As a result, excessive angiotensin II is constantly available for AT1R hyperactivation. […] Therefore, ACE2 exerts protective functions in various RAS-based pathogenesis models involving acute and chronic inflammation. […] SARS-CoV-2-induced ACE2 deficiency can also antagonize the anti-inflammatory properties of angiotensin 17. […] Thus, SARS-CoV-2-induced ACE2 deficiency can also antagonize the anti-inflammatory properties of angiotensin 17. […] The cytokine storm induced by SARS-CoV-2 infection can be regarded as a self-elicited and suicidal systemic immunological reaction that can adversely affect every key organ in the body. […] COVID-19 pathogenesis stage-specific therapeutics should be selected to maximize patient recovery and survival.

• #74 COVID-19 infection: an overview on cytokine storm and related interventions | Virology Journal | Full Text

  https://virologyj.biomedcentral.com/articles/10.1186/s12985-022-01814-1

  With this evidence, a great deal of attention has been paid to dampening signaling pathways of inflammatory cytokines aiming to reduce inflammatory responses and mortality in patients suffering from COVID-19. […] Given the essential role of IL-6 as a key driver in inflammatory status, and based on international guidelines, finding a suitable and efficient approach to inhibit IL-6 signaling is in demand. […] Recent evidence has implied the possible role of the inflammatory cytokines in the pathology of severe COVID-19. […] The role of IL-1 in the pathogenesis of COVID-19; hence, blocking IL-1-mediated activity is a reasonable therapeutic strategy. […] It is well documented that the release of IL-1 mainly depends on the expression of the (NLR family pyrin domain containing 3) NLRP3 inflammasome, which controls the maturation of IL-1.

• #75 COVID-19 infection: an overview on cytokine storm and related interventions | Virology Journal | Full Text

  https://virologyj.biomedcentral.com/articles/10.1186/s12985-022-01814-1

  Based on the IL-1-mediated inflammatory responses, it can be assumed that IL-1-mediated inflammation is responsible for the development of COVID-19 pathogenesis. […] It has been well established that the JAK-STAT pathway mediates the differentiation of Th17 cells. The signals from IL-6 and IL-23 can cause TH17 cell polarization from nave CD4+. […] Given the profound role of excessive TNF in the development, pathogenesis, and poor outcome of COVID-19, blockade of TNF offers a clinically effective intervention in this regard.

• #76 COVID-19: Coronavirus replication, pathogenesis, and therapeutic strategies | Cleveland Clinic Journal of Medicine

  https://www.ccjm.org/content/87/6/321

  Severe disease is associated with lymphopenia and an uncontrolled systemic inflammatory response called a cytokine storm, which ultimately leads to multiple organ failure and death. […] Autopsy results reveal severe damage to endothelial tissue, vasculitis-like manifestations, and atrophy of secondary lymphoid tissues. […] The emergence of 3 highly pathogenic human coronaviruses within the past 20 years predicts that more of them will continue to come along. […] Clinical trials with drugs targeting viral proteins will reveal tolerance of the SARS-CoV-2 to selective pressure and guide in development of strategies that target host proteins required for replication.

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