Materiały źródłowe

• #1 A new mechanism by which rotavirus makes you sick

  https://medicalxpress.com/news/2023-12-mechanism-rotavirus-sick.html

  Rotavirus causes gastroenteritis, a condition that includes diarrhea, deficient nutrient absorption and weight loss. Severe cases result in approximately 128,000 deaths annually in infants and children worldwide. […] Despite intense research on how rotavirus causes diarrhea, there is still no complete answer, but in this new study researchers at Baylor College of Medicine report a new mechanism by which rotavirus induces diarrhea, interfering with the normal absorption of nutrients in the intestine. […] The study, published in Proceedings of the National Academy of Sciences, is the first to show that rotavirus-altered lipid metabolism in the intestine plays a role in the disease. Rotavirus infection leads to the degradation of DGAT1, an enzyme involved in normal lipid droplet formation in intestinal cells, which in turn reduces the production of key nutrient transporters and other proteins required for normal intestinal nutrient absorption, leading to diarrhea.

• #2 Pathogenesis of Intestinal and Systemic Rotavirus Infection

  https://pmc.ncbi.nlm.nih.gov/articles/PMC516399/

  Rotaviruses are responsible for significant gastrointestinal disease, primarily in children 5 years of age and the young of other mammalian species. […] Our understanding of rotavirus-induced diarrheal disease is incomplete compared to that of several other pathogens (e.g., cholera). Rotavirus diarrhea has been attributed to several different mechanisms, including malabsorption secondary to enterocyte destruction, a virus-encoded toxin, stimulation of the enteric nervous system (ENS), and villus ischemia. […] Recent studies confirm sporadic case reports that rotavirus infection is not confined to the intestine as was generally assumed. […] Our understanding of rotavirus pathophysiology comes primarily from animal models. Rotaviruses replicate in the nondividing mature enterocytes near the tips of the villi, suggesting that differentiated enterocytes express factors required for efficient infection and replication.

• #3 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Rotavirus-Mechanisms.aspx

  Rotavirus is the dominant cause of infant gastroenteritis worldwide and is associated with substantial mortality in developing countries. […] Despite its significant clinical importance, the pathophysiological mechanisms by which rotavirus induces fluid and electrolyte secretion are still not fully understood. […] The mechanism that causes vomiting, which is characteristic of the early illness, is poorly understood. It may be the result of delayed gastric emptying or early cytokine release acting centrally. […] Studies of rotavirus infection of polarized intestinal epithelial cells demonstrate that these viruses infect cells differently, depending on whether or not they require sialic acid for initial binding, and the infection can alter epithelial cell functions. […] Upon binding, the virus enters human cells via receptor-mediated endocytosis and forms a vesicle known as an endosome.

• #4 Pathogenesis of Rotavirus diarrhea

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7128947/

  Rotavirus diarrhea is a major cause of infantile gastroenteritis worldwide. This review is mainly devoted to the effects of Rotavirus on intestinal epithelial transport and to the pathophysiological mechanisms proposed to underlie the intestinal fluid secretion caused by the virus. […] This review is devoted to Rotavirus-induced enteric infection, and in particular, to the pathophysiological mechanisms proposed to underlie the intestinal fluid secretion caused by the virus. […] Several of the Rotavirus genes have been associated with their ability to cause disease. The non-structural proteins NSP1, NSP2 and NSP4 are believed to be involved in virulence in mice and the structural proteins vp3 and vp7 in pigs. […] Rotavirus infects the mature enterocytes in the mid and upper part of the villi of the small intestine, which ultimately leads to diarrhea. Current information indicates that Rotavirus attachment and entry into cells constitute a multistep process.

• #5 Pathogenesis of Intestinal and Systemic Rotavirus Infection

  https://pmc.ncbi.nlm.nih.gov/articles/PMC516399/

  Rotaviruses are responsible for significant gastrointestinal disease, primarily in children 5 years of age and the young of other mammalian species. […] Our understanding of rotavirus-induced diarrheal disease is incomplete compared to that of several other pathogens (e.g., cholera). Rotavirus diarrhea has been attributed to several different mechanisms, including malabsorption secondary to enterocyte destruction, a virus-encoded toxin, stimulation of the enteric nervous system (ENS), and villus ischemia. […] Recent studies confirm sporadic case reports that rotavirus infection is not confined to the intestine as was generally assumed. […] Our understanding of rotavirus pathophysiology comes primarily from animal models. Rotaviruses replicate in the nondividing mature enterocytes near the tips of the villi, suggesting that differentiated enterocytes express factors required for efficient infection and replication.

• #6 Rotaviruses: From Pathogenesis to Disease Control—A Critical Review

  https://www.mdpi.com/1999-4915/14/5/875

  Rotaviruses target and infect mature, non-dividing absorptive villous epithelium of the upper two-thirds of the small intestine. The initial viral–host interaction is facilitated by the binding of outer capsid protein VP4 (through its VP8* domain) and host cell receptors, which include the sialoglycans (such as gangliosides GM1 and GD1a) and histo-blood group antigens (HBGAs). The interaction via polymorphic HBGA in red blood cells, mucosal secretions, and epithelia is biased by a particular rotavirus P genotype. The HBGA are complex glycans that are catalyzed by glycosyltransferases through series of monosaccharides addition to an initial precursor. The enzyme expression is controlled by the AB0, FUT2 (secretor), and FUT3 (lewis) genes, and both in vivo and in vitro studies have demonstrated their presence as a marker of host susceptibility to several infectious diseases including group A RV. The genetic differentials in HBGA expression have been likened to variations in rotavirus epidemiology among human populations and infection with different RV genotypes. For example, genotype P[8] and P[4] preferentially bind to the Lewis b and H type-1 (H1) antigens, genotypes P[9], P[14], and P[25] bind to type A antigens, while P[11] selectively binds to the type-2 precursor glycan. Findings from a meta-analysis indicated a strong association between HBGA expression and susceptibility to natural infection by P[8] rotaviruses.

• #7 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Rotavirus-Mechanisms.aspx

  Rotavirus is the dominant cause of infant gastroenteritis worldwide and is associated with substantial mortality in developing countries. […] Despite its significant clinical importance, the pathophysiological mechanisms by which rotavirus induces fluid and electrolyte secretion are still not fully understood. […] The mechanism that causes vomiting, which is characteristic of the early illness, is poorly understood. It may be the result of delayed gastric emptying or early cytokine release acting centrally. […] Studies of rotavirus infection of polarized intestinal epithelial cells demonstrate that these viruses infect cells differently, depending on whether or not they require sialic acid for initial binding, and the infection can alter epithelial cell functions. […] Upon binding, the virus enters human cells via receptor-mediated endocytosis and forms a vesicle known as an endosome.

• #8 Pathogenesis of Rotavirus diarrhea

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7128947/

  The Ca2+-dependent endocytosis process represents the most attractive mode of entry and is based on the fact that infectious Rotavirus is endocytosed into the cytoplasm with a very low Ca2+ concentration that leads to a Ca2+ afflux from the vesicles to the cytoplasm. […] A symptomatic infection with Rotavirus stimulates a strong humoral IgG immune response which lasts for the lifetime. […] The pathophysiological mechanisms underlying the fluid losses seen in different types of diarrhea have been debated for decades. […] The demonstration that cholera toxin evoked an increase in intracellular cAMP concentration represented a major breakthrough at the time. […] The experimental evidence for a diminished absorptive capacity of fluid, electrolytes, glucose and amino acids in Rotavirus-infected intestines was reviewed above when describing the morphological and functional effects of the virus.

• #9 Rotavirus Replication: Gaps of Knowledge on Virus Entry and Morphogenesis

  https://www.jstage.jst.go.jp/article/tjem/248/4/248_285/_html/-char/en

  In the case of RVs, findings have suggested two methods for virus entry and virion assembly. […] RV attachment is a complex process; however, progress is being made owing to new molecular and structural information on the outer capsid proteins and an understanding of differences in virus strains. […] The TLP interacts via its VP4 spikes with cellular receptors (attachment receptors), which contain sialic acid (SA) at terminal or sub-terminal positions. […] RVs are internalized into cells by clathrin-dependent or -independent endocytic pathways, depending on the virus strain. […] It has been proposed that, at the exit of TLP from the endosomal compartment, the RV spike protein VP4 undergoes an initial conformational change, triggered by unknown factors. […] The loss of outer capsid VP7 activates the internal polymerase complex to transcribe capped positive-sense RNA [(+) RNA] from each of the 11 dsRNA genome segments for release into the cytosol.

• #10 Rotaviruses: From Pathogenesis to Disease Control—A Critical Review

  https://www.mdpi.com/1999-4915/14/5/875

  In the post-attachment stage, the trypsin-like proteases of the gastrointestinal tract proteolytically cleave VP4 spike into VP8 and VP5, a highly ordered conformational change in the capsid proteins and an important event that accelerates viral penetration, thus promoting infectivity. RV infection is largely localized to the intestinal mucosa, although evidence of viral replication has been shown in some distant areas of the body such as lamina propria and regional lymphatics, especially among the immunocompromised individuals. Viral replication at these extraintestinal sites and systemic spread is usually rare in immunologically competent persons. Rotaviral diarrhea is caused by multiple activities of the virus. One mechanism is that the extensive replication of the virus coupled with massive cellular necrosis of the gut epithelium causes villous atrophy, loss of microvilli, severe mononuclear cell infiltration, endoplasmic reticulum and mitochondrial engorgement in enterocytes, and loss of intestinal brush border enzymes such as maltase, sucrase, and lactase. The result of this is nutrients, electrolytes, and fluid malabsorption leading to increased osmotic pressure in the gut lumen and subsequently onset of diarrhea. Reactive crypt-cell hyperplasia following the process may accelerate rates of fluid secretion, thereby increasing the severity of diarrhea.

• #11 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Rotavirus-Mechanisms.aspx

  Proteins in the outer layer of the virus, which are known as VP7 and VP4 spike, disrupt the membrane of the endosome, which creates a difference in calcium concentrations. […] This results in the breakdown of VP7 trimers into single protein subunits and the formation of a double-layered particle. […] The RNA-dependent RNA polymerase of the virus creates messenger RNA (mRNA) transcripts of the double-stranded viral genome. […] By remaining in the core, the viral RNA evades innate host immune responses through a process known as RNA interference that is triggered by the presence of double-stranded RNA. […] Rotavirus infection alters the function of the small intestinal epithelium, resulting in diarrhea. […] The mechanism of diarrhea is multicomponent in nature and results from the direct effects of the virus infection itself, as well as the indirect effects of infection and the host response.

• #12 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Rotavirus-Mechanisms.aspx

  Proteins in the outer layer of the virus, which are known as VP7 and VP4 spike, disrupt the membrane of the endosome, which creates a difference in calcium concentrations. […] This results in the breakdown of VP7 trimers into single protein subunits and the formation of a double-layered particle. […] The RNA-dependent RNA polymerase of the virus creates messenger RNA (mRNA) transcripts of the double-stranded viral genome. […] By remaining in the core, the viral RNA evades innate host immune responses through a process known as RNA interference that is triggered by the presence of double-stranded RNA. […] Rotavirus infection alters the function of the small intestinal epithelium, resulting in diarrhea. […] The mechanism of diarrhea is multicomponent in nature and results from the direct effects of the virus infection itself, as well as the indirect effects of infection and the host response.

• #13

  https://www.healio.com/news/pediatrics/20120331/rotavirus-replication-pathogenesis-and-vaccine-development

  Rotaviruses cause approximately 600,000 deaths worldwide in children younger than five each year. […] Researchers reported in the July 17, 2009, issue of Science that rotavirus vaccination should prevent or lessen the frequency of rotavirus outbreaks, as well as increase the age at which rotavirus presents for the first time in children. […] Understanding the genomic function and makeup of rotavirus proved to be a key factor in the development of rotavirus vaccines. […] „Production of mRNA for protein synthesis is one of the first occurrences when a virus infects a cell.” […] Unlike DNA viruses, a rotavirus conducts its lifecycle in the cytoplasm, never moving into the nucleus. […] „The new resulting reassortant viruses will have picked up some segments from one virus and other segments from the co-infecting virus.”

• #14 Rotavirus-Mediated DGAT1 Degradation: A Pathophysiological Mechanism of Viral-Induced Malabsorptive Diarrhea

  https://digitalcommons.library.tmc.edu/baylor_docs/1697/

  Gastroenteritis is among the leading causes of mortality globally in infants and young children, with rotavirus (RV) causing ~258 million episodes of diarrhea and ~128,000 deaths annually in infants and children. […] RV alters cellular lipid metabolism by inducing lipid droplet (LD) formation as a platform for replication factories named viroplasms. […] We found that diacylglycerol O-acyltransferase 1 (DGAT1), the terminal step in triacylglycerol synthesis required for LD biogenesis, is degraded in RV-infected cells by a proteasome-mediated mechanism. […] RV-infected DGAT1-silenced cells show earlier and increased numbers of LD-associated viroplasms per cell that translate into a fourfold-to-fivefold increase in viral yield.

• #15 Pathogenesis of Intestinal and Systemic Rotavirus Infection

  https://pmc.ncbi.nlm.nih.gov/articles/PMC516399/

  Rotavirus infection alters the function of the small intestinal epithelium, resulting in diarrhea. The diarrhea was generally considered to be malabsorptive, secondary to enterocyte destruction. […] The NSP4 enterotoxin activity provides a way to mediate diarrheagenic changes in the absence of significant damage or to mediate changes at uninfected sites. […] Thus, it is clear that rotavirus diarrhea is multifactoral, resulting from the direct effects of virus infection and the indirect effects of infection and the host response. […] The process leading to diarrhea is initiated when rotavirus binds to and infects enterocytes in the small intestine. […] The release of NSP4 from infected cells allows paracrine effects to occur on uninfected cells. […] The secretory component of rotavirus diarrhea appears to be secondary to virus-induced functional changes at the villus epithelium.

• #16 Rotaviruses: From Pathogenesis to Disease Control—A Critical Review

  https://www.mdpi.com/1999-4915/14/5/875

  In the post-attachment stage, the trypsin-like proteases of the gastrointestinal tract proteolytically cleave VP4 spike into VP8 and VP5, a highly ordered conformational change in the capsid proteins and an important event that accelerates viral penetration, thus promoting infectivity. RV infection is largely localized to the intestinal mucosa, although evidence of viral replication has been shown in some distant areas of the body such as lamina propria and regional lymphatics, especially among the immunocompromised individuals. Viral replication at these extraintestinal sites and systemic spread is usually rare in immunologically competent persons. Rotaviral diarrhea is caused by multiple activities of the virus. One mechanism is that the extensive replication of the virus coupled with massive cellular necrosis of the gut epithelium causes villous atrophy, loss of microvilli, severe mononuclear cell infiltration, endoplasmic reticulum and mitochondrial engorgement in enterocytes, and loss of intestinal brush border enzymes such as maltase, sucrase, and lactase. The result of this is nutrients, electrolytes, and fluid malabsorption leading to increased osmotic pressure in the gut lumen and subsequently onset of diarrhea. Reactive crypt-cell hyperplasia following the process may accelerate rates of fluid secretion, thereby increasing the severity of diarrhea.

• #17 Clinical manifestations and diagnosis of rotavirus infection – UpToDate

  https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-rotavirus-infection/print

  Before national vaccination programs, rotaviruses were among the first viral agents identified as important causes of viral gastroenteritis, particularly in children between the ages of six months and two years. […] The pathogenesis, epidemiology, clinical manifestations, and diagnosis of rotavirus gastroenteritis will be reviewed here. […] Pathogenesis – At least three factors are thought to play a role in the pathogenesis of rotavirus-induced diarrhea: […] Necrosis of the gut epithelium leading to villous atrophy and loss of microvilli, mononuclear cell infiltration, endoplasmic reticulum and mitochondrial engorgement in enterocytes, and loss of intestinal brush border enzymes (eg, maltase, sucrase, lactase).

• #18 Chapter 19: Rotavirus | Pink Book | CDC

  https://www.cdc.gov/pinkbook/hcp/table-of-contents/chapter-19-rotavirus.html

  The virus enters the body through the mouth. Viral replication occurs in the villous epithelium of the small intestine. Up to two-thirds of children with severe rotavirus gastroenteritis show the presence of rotavirus antigen in serum (antigenemia) and children can have rotavirus RNA detected in serum. […] Infection may result in decreased intestinal absorption of sodium, glucose, and water, and decreased levels of intestinal lactase, alkaline phosphatase, and sucrase activity, and may lead to isotonic diarrhea. […] The immune correlates of protection from rotavirus are not fully understood. Serum and mucosal antibodies against VP7 and VP4 are probably important for protection from disease. Cell-mediated immunity probably plays a role in protection and in recovery from infection.

• #19 Rotavirus | PPT

  https://www.slideshare.net/slideshow/rotavirus/3967887

  Rotavirus is a common cause of diarrhea in infants and children worldwide. […] The virus attaches to and damages cells lining the intestines, causing watery diarrhea that can lead to dehydration. […] The virus infects the villi of the small intestine. […] They multiply in the cytoplasm of the enterocytes and damage their transport mechanisms. […] Damaged cells on villi are replaced by non absorbing immature cells. […] Watery diarrhea due to net secretion of intestinal fluid and loss of absorptive surface. […] Activation of the enteric nervous system. […] Role of NSP4 peptide regions as an enterotoxin. […] The virus is stable in the environment. […] They strip the tips of the villi thus decreasing the surface area and decreasing by more than 50% the specific absorptive capacities of the intestine. […] Infection leads to isotonic diarrhea. […] Viral attachment, multiplication and release.

• #20 Rotaviruses: From Pathogenesis to Disease Control—A Critical Review

  https://www.mdpi.com/1999-4915/14/5/875

  In the post-attachment stage, the trypsin-like proteases of the gastrointestinal tract proteolytically cleave VP4 spike into VP8 and VP5, a highly ordered conformational change in the capsid proteins and an important event that accelerates viral penetration, thus promoting infectivity. RV infection is largely localized to the intestinal mucosa, although evidence of viral replication has been shown in some distant areas of the body such as lamina propria and regional lymphatics, especially among the immunocompromised individuals. Viral replication at these extraintestinal sites and systemic spread is usually rare in immunologically competent persons. Rotaviral diarrhea is caused by multiple activities of the virus. One mechanism is that the extensive replication of the virus coupled with massive cellular necrosis of the gut epithelium causes villous atrophy, loss of microvilli, severe mononuclear cell infiltration, endoplasmic reticulum and mitochondrial engorgement in enterocytes, and loss of intestinal brush border enzymes such as maltase, sucrase, and lactase. The result of this is nutrients, electrolytes, and fluid malabsorption leading to increased osmotic pressure in the gut lumen and subsequently onset of diarrhea. Reactive crypt-cell hyperplasia following the process may accelerate rates of fluid secretion, thereby increasing the severity of diarrhea.

• #21 Rotavirus- An Overview

  https://microbenotes.com/rota-virus/

  Rotaviruses infect cells in the villi of the small intestine. […] They multiply in the cytoplasm of enterocytes and damage their transport mechanisms. […] Rotavirus infection prevents the absorption of water, causing a net secretion of water and loss of ions, which together result in watery diarrhea. […] The NSP4 protein of rotavirus acts in a toxin-like manner to promote calcium ion influx into enterocytes, the release of neuronal activators, and a neuronal alteration in water absorption. […] The loss of fluids and electrolytes can lead to severe dehydration and even death if therapy does not include electrolyte replacement. […] Diarrhea caused by rotaviruses may also be due to impaired sodium and glucose absorption as damaged cells on villi are replaced by nonabsorbing immature crypt cells.

• #22 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Rotavirus-Mechanisms.aspx

  Therefore, diarrhea may be caused by several mechanisms, including malabsorption that occurs secondary to the destruction of enterocytes, villus ischemia, activation of the enteric nervous system, as well as intestinal secretion stimulated by the intracellular or extracellular action of the rotavirus non-structural protein NSP4. […] The NSP4 protein of rotavirus, which has been described as the first viral enterotoxin, has a significant role in causing diarrhea. […] This enterotoxin induces diarrheal response, stimulates calcium-dependent cell permeability, and alters epithelial cell integrity. […] One of the main effects of rotaviral infection is a decrease in intestinal disaccharidase activities with a relatively intact intestinal brush border membrane. […] NSP4 can specifically perturb the paracellular permeability to various molecules, reorganize filamentous actin filaments, and prevent transport of the Zona Occludens-1 (ZO-1) protein to tight junctions.

• #23 Pathogenesis of Rotavirus diarrhea

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7128947/

  One of the non-structural proteins of Rotavirus, NSP4, is a transmembrane, endoplasmatic reticulum-specific glycoprotein. […] The main body of experiments with NSP4 residues 114135 suggest that it may function as a virus enterotoxin at least in mice. […] Several observations made during Rotavirus enteritis in neonatal mice suggest that the secretory response is in part explained by an activation of the ENS.

• #24 Rotaviruses: From Pathogenesis to Disease Control—A Critical Review

  https://www.mdpi.com/1999-4915/14/5/875

  A second mechanism underlying RV diarrhea is that viral enterotoxin NSP4 produced by RV-infected cells binds to intestinal epithelial cells and signals through phospholipase C, thereby activating signaling pathways that can induce age- and calcium ion-dependent chloride secretion into the intestinal lumen. High chloride ion concentration provides an osmotic gradient that favors the movement of water into the intestinal lumen that ultimately results in secretory diarrhea. The NSP4 protein inactivates the Sodium-Glucose-Lactose-Transporter proteins system (SGLT1) that mediates reabsorption of water, sugar, and body electrolytes, thereby reducing the activity of brush-border membrane disaccharidases and perhaps activation of the calcium ion-dependent secretory reflexes of the enteric nervous system as well as the loss of water from the body.

• #25 Rotaviruses: From Pathogenesis to Disease Control—A Critical Review

  https://www.mdpi.com/1999-4915/14/5/875

  A second mechanism underlying RV diarrhea is that viral enterotoxin NSP4 produced by RV-infected cells binds to intestinal epithelial cells and signals through phospholipase C, thereby activating signaling pathways that can induce age- and calcium ion-dependent chloride secretion into the intestinal lumen. High chloride ion concentration provides an osmotic gradient that favors the movement of water into the intestinal lumen that ultimately results in secretory diarrhea. The NSP4 protein inactivates the Sodium-Glucose-Lactose-Transporter proteins system (SGLT1) that mediates reabsorption of water, sugar, and body electrolytes, thereby reducing the activity of brush-border membrane disaccharidases and perhaps activation of the calcium ion-dependent secretory reflexes of the enteric nervous system as well as the loss of water from the body.

• #26 Rotavirus – Wikipedia

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

  Rotaviruses replicate mainly in the gut, and infect enterocytes of the villi of the small intestine, leading to structural and functional changes of the epithelium. […] The diarrhoea is caused by multiple activities of the virus. Malabsorption occurs because of the destruction of gut cells called enterocytes. The toxic rotavirus protein NSP4 induces age- and calcium ion-dependent chloride secretion, disrupts SGLT1 (sodium/glucose cotransporter 2) transporter-mediated reabsorption of water, apparently reduces activity of brush-border membrane disaccharidases, and activates the calcium ion-dependent secretory reflexes of the enteric nervous system. […] NSP4 is also secreted. This extracellular form, which is modified by protease enzymes in the gut, is an enterotoxin which acts on uninfected cells via integrin receptors, which in turn cause and increase in intracellular calcium ion concentrations, secretory diarrhoea and autophagy.

• #27 Rotaviruses: From Pathogenesis to Disease Control—A Critical Review

  https://www.mdpi.com/1999-4915/14/5/875

  A second mechanism underlying RV diarrhea is that viral enterotoxin NSP4 produced by RV-infected cells binds to intestinal epithelial cells and signals through phospholipase C, thereby activating signaling pathways that can induce age- and calcium ion-dependent chloride secretion into the intestinal lumen. High chloride ion concentration provides an osmotic gradient that favors the movement of water into the intestinal lumen that ultimately results in secretory diarrhea. The NSP4 protein inactivates the Sodium-Glucose-Lactose-Transporter proteins system (SGLT1) that mediates reabsorption of water, sugar, and body electrolytes, thereby reducing the activity of brush-border membrane disaccharidases and perhaps activation of the calcium ion-dependent secretory reflexes of the enteric nervous system as well as the loss of water from the body.

• #28 Rotaviruses: From Pathogenesis to Disease Control—A Critical Review

  https://www.mdpi.com/1999-4915/14/5/875

  A second mechanism underlying RV diarrhea is that viral enterotoxin NSP4 produced by RV-infected cells binds to intestinal epithelial cells and signals through phospholipase C, thereby activating signaling pathways that can induce age- and calcium ion-dependent chloride secretion into the intestinal lumen. High chloride ion concentration provides an osmotic gradient that favors the movement of water into the intestinal lumen that ultimately results in secretory diarrhea. The NSP4 protein inactivates the Sodium-Glucose-Lactose-Transporter proteins system (SGLT1) that mediates reabsorption of water, sugar, and body electrolytes, thereby reducing the activity of brush-border membrane disaccharidases and perhaps activation of the calcium ion-dependent secretory reflexes of the enteric nervous system as well as the loss of water from the body.

• #29 Rotavirus – Wikipedia

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

  Rotaviruses replicate mainly in the gut, and infect enterocytes of the villi of the small intestine, leading to structural and functional changes of the epithelium. […] The diarrhoea is caused by multiple activities of the virus. Malabsorption occurs because of the destruction of gut cells called enterocytes. The toxic rotavirus protein NSP4 induces age- and calcium ion-dependent chloride secretion, disrupts SGLT1 (sodium/glucose cotransporter 2) transporter-mediated reabsorption of water, apparently reduces activity of brush-border membrane disaccharidases, and activates the calcium ion-dependent secretory reflexes of the enteric nervous system. […] NSP4 is also secreted. This extracellular form, which is modified by protease enzymes in the gut, is an enterotoxin which acts on uninfected cells via integrin receptors, which in turn cause and increase in intracellular calcium ion concentrations, secretory diarrhoea and autophagy.

• #30 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Rotavirus-Mechanisms.aspx

  Therefore, diarrhea may be caused by several mechanisms, including malabsorption that occurs secondary to the destruction of enterocytes, villus ischemia, activation of the enteric nervous system, as well as intestinal secretion stimulated by the intracellular or extracellular action of the rotavirus non-structural protein NSP4. […] The NSP4 protein of rotavirus, which has been described as the first viral enterotoxin, has a significant role in causing diarrhea. […] This enterotoxin induces diarrheal response, stimulates calcium-dependent cell permeability, and alters epithelial cell integrity. […] One of the main effects of rotaviral infection is a decrease in intestinal disaccharidase activities with a relatively intact intestinal brush border membrane. […] NSP4 can specifically perturb the paracellular permeability to various molecules, reorganize filamentous actin filaments, and prevent transport of the Zona Occludens-1 (ZO-1) protein to tight junctions.

• #31 Rotavirus – Wikipedia

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

  Rotaviruses replicate mainly in the gut, and infect enterocytes of the villi of the small intestine, leading to structural and functional changes of the epithelium. […] The diarrhoea is caused by multiple activities of the virus. Malabsorption occurs because of the destruction of gut cells called enterocytes. The toxic rotavirus protein NSP4 induces age- and calcium ion-dependent chloride secretion, disrupts SGLT1 (sodium/glucose cotransporter 2) transporter-mediated reabsorption of water, apparently reduces activity of brush-border membrane disaccharidases, and activates the calcium ion-dependent secretory reflexes of the enteric nervous system. […] NSP4 is also secreted. This extracellular form, which is modified by protease enzymes in the gut, is an enterotoxin which acts on uninfected cells via integrin receptors, which in turn cause and increase in intracellular calcium ion concentrations, secretory diarrhoea and autophagy.

• #32 Rotaviruses: From Pathogenesis to Disease Control—A Critical Review

  https://www.mdpi.com/1999-4915/14/5/875

  Under normalcy, healthy enterocytes secrete lactase into the small intestine that helps in lactose metabolism, but children with rotavirus infection are unable to tolerate milk due to lactase deficiency that can last for several weeks. Such a child may experience recurrence of diarrhea after milk reintroduction into the child’s diet as a result of bacterial fermentation of the lactose in the gut. A third mechanism is based on the stimulation of the enteric nervous system by the viral enterotoxin. The NSP4-mediated increase in intracellular calcium concentration induces the secretion of 5-hydroxytryptamine (5-HT) also called serotonin from enteroendocrine cells in humans. This chemical triggers the activation of enteric nerves that innervate the small intestine, thereby increasing intestinal motility, which is associated with diarrheal onset.

• #33 Rotavirus infection | Nature Reviews Disease Primers

  https://www.nature.com/articles/nrdp201783

  Rotavirus primarily infects enterocytes and induces diarrhoea through the destruction of absorptive enterocytes (leading to malabsorption), intestinal secretion stimulated by rotavirus non-structural protein 4 and activation of the enteric nervous system. […] In addition, rotavirus infections can lead to antigenaemia (which is associated with more severe manifestations of acute gastroenteritis) and viraemia, and rotavirus can replicate in systemic sites, although this is limited. […] The immune correlates of protection against rotavirus reinfection and recovery from infection are poorly understood, although rotavirus-specific immunoglobulin A has a role in both aspects. […] Rotavirus stimulates release of serotonin (5-HT) from human enterochromaffin cells and activates brain structures involved in nausea and vomiting.

• #34 Rotaviruses: From Pathogenesis to Disease Control—A Critical Review

  https://www.mdpi.com/1999-4915/14/5/875

  Evidence studies have shown that drugs that block such stimulation were associated with the alleviation of diarrhea. The mechanisms that trigger vomiting usually seen in an early illness may be the result of early cytokine release acting centrally, or delayed gastric emptying. Whether the latter is a result of an increase in gastrointestinal hormones (e.g., secretin, gastrin, and cholecystokinin) or vagal nerves activation associated with rotavirus infection remains an area for future study to look at. […] RV infection has been linked to systemic diseases such as seizures in the CNS, acute cerebellitis, and autoimmune pathology with clinical and pathophysiological implications beyond the gut. One suggested mechanism of viral spread from the gut to CNS is that viral attachment to specific surface receptors such as histo-blood antigens, sialic acids, and integrins may be followed by the crossing of the blood–brain barrier. The CNS has been identified as one of the main targets of extraintestinal infection, a reason attributed to rotavirus tropism toward the neuronal cells. Antigenemia and viremia are commonly found in children infected with RV even when diarrhea is not detected. Patient with such condition has manifested with increased severity in terms of fever, vomiting or convulsion, although the underlying mechanism is yet to be unraveled.

• #35

  https://link.springer.com/article/10.1007/s11302-021-09773-y

  Rotavirus (RV) infection causes life-threatening diarrhea, despite only infecting a limited number of intestinal cells. […] However, the mechanisms of RV-induced signaling changes are multifactorial and incompletely understood. […] Here, by combining sophisticated long-term live fluorescent imaging techniques and CRISPR technology in simian- and human-derived cell cultures, the authors show that RV-infected cells signal to surrounding uninfected cells through a purinergic signaling pathway. […] This process is driven by adenosine diphosphate (ADP) release from RV-infected cells and its subsequent interaction with P2Y1 receptors expressed by neighboring cells. […] This mechanism appears to be independent of traditional RV-induced signaling pathways that involve paracrine signaling molecules such as prostaglandin E-2 (PGE2), nitric oxide (NO), or RV enterotoxin nonstructural protein 4 (NSP4).

• #36

  https://link.springer.com/article/10.1007/s11302-021-09773-y

  Purinergic signaling through P2Y1 receptors also contributes to diarrhea by stimulating serotonin (5-HT) secretion from RV-infected cells, and small molecule inhibitors of P2Y1 receptors reduced diarrhea severity in infected animals. […] Thus, P2Y1-ADP signaling is a promising target for future RV infection therapies. […] RV induces major alterations to host cell homeostasis which result in the release of potent paracrine signaling molecules including enterotoxin NSP4, PGE2, and NO. […] These paracrine signals are linked to dysregulated serotonergic signaling and enteric modulated secretory function in the gastrointestinal (GI) tract. […] Virally encoded NSP4 is responsible for inducing ICWs in RV-infected cells and is, therefore, the usual suspect for disease onset and progression.

• #37 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20231211/Study-reveals-new-mechanism-by-which-rotavirus-induces-diarrhea.aspx

  Rotavirus causes gastroenteritis, a condition that includes diarrhea, deficient nutrient absorption and weight loss. Severe cases result in approximately 128,000 deaths annually in infants and children worldwide. […] in this new study researchers at Baylor College of Medicine report a new mechanism by which rotavirus induces diarrhea, interfering with the normal absorption of nutrients in the intestine. […] The study, published in Proceedings of the National Academy of Sciences, is the first to show that rotavirus-altered lipid metabolism in the intestine plays a role in the disease. Rotavirus infection leads to the degradation of DGAT1, an enzyme involved in normal lipid droplet formation in intestinal cells, which in turn reduces the production of key nutrient transporters and other proteins required for normal intestinal nutrient absorption, leading to diarrhea.

• #38 A new mechanism by which rotavirus makes you sick | BCM

  https://www.bcm.edu/news/a-new-mechanism-by-which-rotavirus-makes-you-sick

  Rotavirus causes gastroenteritis, a condition that includes diarrhea, deficient nutrient absorption and weight loss. […] in this new study researchers at Baylor College of Medicine report a new mechanism by which rotavirus induces diarrhea, interfering with the normal absorption of nutrients in the intestine. […] Rotavirus infection leads to the degradation of DGAT1, an enzyme involved in normal lipid droplet formation in intestinal cells, which in turn reduces the production of key nutrient transporters and other proteins required for normal intestinal nutrient absorption, leading to diarrhea. […] we discovered that rotavirus binds to and breaks down or degrades DGAT1, an enzyme that contributes to the formation of the lipid droplets. […] This led us to think that rotavirus-mediated degradation of DGAT1 could be a mechanism by which the virus induces diarrhea.

• #39 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20231211/Study-reveals-new-mechanism-by-which-rotavirus-induces-diarrhea.aspx

  „But we found a new mechanism by which rotavirus induces diarrhea. Like the children who have a genetic DGAT1 deficiency that causes diarrhea, when rotavirus degrades DGAT1 the result is reduced production of the enzymes that are involved in degrading the food we eat and disruption of the mechanisms that transport nutrients into cells, which leads to diarrhea,” Smith said. […] „It was very unexpected that rotavirus has a protein that interacts with and degrades DGAT1 and that eliminating DGAT1 would lead to all these downstream effects that would cause diarrhea,” Crawford said. […] „It was very surprising that a rotavirus protein that until now was only known to be important for the virus to replicate, also plays a role in causing diarrhea, a major component of the disease.”

• #40 A new mechanism by which rotavirus makes you sick

  https://medicalxpress.com/news/2023-12-mechanism-rotavirus-sick.html

  „But we found a new mechanism by which rotavirus induces diarrhea. Like the children who have a genetic DGAT1 deficiency that causes diarrhea, when rotavirus degrades DGAT1 the result is reduced production of the enzymes that are involved in degrading the food we eat and disruption of the mechanisms that transport nutrients into cells, which leads to diarrhea,” Smith said. […] „It was very surprising that a rotavirus protein that until now was only known to be important for the virus to replicate, also plays a role in causing diarrhea, a major component of the disease. The fact that it’s not a capsid protein or part of the structure that envelops the genetic material of the virus, as we usually would think, tells us that we should not assume that nonstructural proteins do not play roles in causing disease.”

• #41 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Rotavirus-Mechanisms.aspx

  Rotavirus is the dominant cause of infant gastroenteritis worldwide and is associated with substantial mortality in developing countries. […] Despite its significant clinical importance, the pathophysiological mechanisms by which rotavirus induces fluid and electrolyte secretion are still not fully understood. […] The mechanism that causes vomiting, which is characteristic of the early illness, is poorly understood. It may be the result of delayed gastric emptying or early cytokine release acting centrally. […] Studies of rotavirus infection of polarized intestinal epithelial cells demonstrate that these viruses infect cells differently, depending on whether or not they require sialic acid for initial binding, and the infection can alter epithelial cell functions. […] Upon binding, the virus enters human cells via receptor-mediated endocytosis and forms a vesicle known as an endosome.

• #42 Rotavirus – Wikipedia

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

  The vomiting, which is a characteristic of rotaviral enteritis, is caused by the virus infecting the enterochromaffin cells on the lining of the digestive tract. The infection stimulates the production of 5′ hydroxytryptamine (serotonin). This activates vagal afferent nerves, which in turn activates the cells of the brain stem that control the vomiting reflex.

• #43 Rotavirus infection | Nature Reviews Disease Primers

  https://www.nature.com/articles/nrdp201783

  This report shows that rotavirus can stimulate 5-HT release from human enterochromaffin cells and activate the vomiting centre in the central nervous system. […] This study uses human intestinal enteroids to study rotavirus infections. […] Rotavirus disrupts calcium homeostasis by NSP4 viroporin activity. […] Rotaviral enterotoxin nonstructural protein 4 targets mitochondria for activation of apoptosis during infection. […] NSP4 enterotoxin of rotavirus induces paracellular leakage in polarized epithelial cells. […] Rotavirus enterotoxin NSP4 binds to the extracellular matrix proteins laminin-3 and fibronectin. […] Rotavirus NSP1 inhibits NFB activation by inducing proteasome-dependent degradation of -TrCP: a novel mechanism of IFN antagonism. […] Comparative proteomics reveals strain-specific -TrCP degradation via rotavirus NSP1 hijacking a host cullin-3-Rbx1 complex. […] Rotavirus NSP1 protein inhibits interferon-mediated STAT1 activation.

• #44 Rotaviruses: From Pathogenesis to Disease Control—A Critical Review

  https://www.mdpi.com/1999-4915/14/5/875

  In the post-attachment stage, the trypsin-like proteases of the gastrointestinal tract proteolytically cleave VP4 spike into VP8 and VP5, a highly ordered conformational change in the capsid proteins and an important event that accelerates viral penetration, thus promoting infectivity. RV infection is largely localized to the intestinal mucosa, although evidence of viral replication has been shown in some distant areas of the body such as lamina propria and regional lymphatics, especially among the immunocompromised individuals. Viral replication at these extraintestinal sites and systemic spread is usually rare in immunologically competent persons. Rotaviral diarrhea is caused by multiple activities of the virus. One mechanism is that the extensive replication of the virus coupled with massive cellular necrosis of the gut epithelium causes villous atrophy, loss of microvilli, severe mononuclear cell infiltration, endoplasmic reticulum and mitochondrial engorgement in enterocytes, and loss of intestinal brush border enzymes such as maltase, sucrase, and lactase. The result of this is nutrients, electrolytes, and fluid malabsorption leading to increased osmotic pressure in the gut lumen and subsequently onset of diarrhea. Reactive crypt-cell hyperplasia following the process may accelerate rates of fluid secretion, thereby increasing the severity of diarrhea.

• #45 Rotaviruses: From Pathogenesis to Disease Control—A Critical Review

  https://www.mdpi.com/1999-4915/14/5/875

  In the post-attachment stage, the trypsin-like proteases of the gastrointestinal tract proteolytically cleave VP4 spike into VP8 and VP5, a highly ordered conformational change in the capsid proteins and an important event that accelerates viral penetration, thus promoting infectivity. RV infection is largely localized to the intestinal mucosa, although evidence of viral replication has been shown in some distant areas of the body such as lamina propria and regional lymphatics, especially among the immunocompromised individuals. Viral replication at these extraintestinal sites and systemic spread is usually rare in immunologically competent persons. Rotaviral diarrhea is caused by multiple activities of the virus. One mechanism is that the extensive replication of the virus coupled with massive cellular necrosis of the gut epithelium causes villous atrophy, loss of microvilli, severe mononuclear cell infiltration, endoplasmic reticulum and mitochondrial engorgement in enterocytes, and loss of intestinal brush border enzymes such as maltase, sucrase, and lactase. The result of this is nutrients, electrolytes, and fluid malabsorption leading to increased osmotic pressure in the gut lumen and subsequently onset of diarrhea. Reactive crypt-cell hyperplasia following the process may accelerate rates of fluid secretion, thereby increasing the severity of diarrhea.

• #46 Rotaviruses: From Pathogenesis to Disease Control—A Critical Review

  https://www.mdpi.com/1999-4915/14/5/875

  Evidence studies have shown that drugs that block such stimulation were associated with the alleviation of diarrhea. The mechanisms that trigger vomiting usually seen in an early illness may be the result of early cytokine release acting centrally, or delayed gastric emptying. Whether the latter is a result of an increase in gastrointestinal hormones (e.g., secretin, gastrin, and cholecystokinin) or vagal nerves activation associated with rotavirus infection remains an area for future study to look at. […] RV infection has been linked to systemic diseases such as seizures in the CNS, acute cerebellitis, and autoimmune pathology with clinical and pathophysiological implications beyond the gut. One suggested mechanism of viral spread from the gut to CNS is that viral attachment to specific surface receptors such as histo-blood antigens, sialic acids, and integrins may be followed by the crossing of the blood–brain barrier. The CNS has been identified as one of the main targets of extraintestinal infection, a reason attributed to rotavirus tropism toward the neuronal cells. Antigenemia and viremia are commonly found in children infected with RV even when diarrhea is not detected. Patient with such condition has manifested with increased severity in terms of fever, vomiting or convulsion, although the underlying mechanism is yet to be unraveled.

• #47 Rotavirus infection | Nature Reviews Disease Primers

  https://www.nature.com/articles/nrdp201783

  Rotavirus primarily infects enterocytes and induces diarrhoea through the destruction of absorptive enterocytes (leading to malabsorption), intestinal secretion stimulated by rotavirus non-structural protein 4 and activation of the enteric nervous system. […] In addition, rotavirus infections can lead to antigenaemia (which is associated with more severe manifestations of acute gastroenteritis) and viraemia, and rotavirus can replicate in systemic sites, although this is limited. […] The immune correlates of protection against rotavirus reinfection and recovery from infection are poorly understood, although rotavirus-specific immunoglobulin A has a role in both aspects. […] Rotavirus stimulates release of serotonin (5-HT) from human enterochromaffin cells and activates brain structures involved in nausea and vomiting.

• #48 Rotaviruses: From Pathogenesis to Disease Control—A Critical Review

  https://www.mdpi.com/1999-4915/14/5/875

  Evidence studies have shown that drugs that block such stimulation were associated with the alleviation of diarrhea. The mechanisms that trigger vomiting usually seen in an early illness may be the result of early cytokine release acting centrally, or delayed gastric emptying. Whether the latter is a result of an increase in gastrointestinal hormones (e.g., secretin, gastrin, and cholecystokinin) or vagal nerves activation associated with rotavirus infection remains an area for future study to look at. […] RV infection has been linked to systemic diseases such as seizures in the CNS, acute cerebellitis, and autoimmune pathology with clinical and pathophysiological implications beyond the gut. One suggested mechanism of viral spread from the gut to CNS is that viral attachment to specific surface receptors such as histo-blood antigens, sialic acids, and integrins may be followed by the crossing of the blood–brain barrier. The CNS has been identified as one of the main targets of extraintestinal infection, a reason attributed to rotavirus tropism toward the neuronal cells. Antigenemia and viremia are commonly found in children infected with RV even when diarrhea is not detected. Patient with such condition has manifested with increased severity in terms of fever, vomiting or convulsion, although the underlying mechanism is yet to be unraveled.

• #49 Pathogenesis of Rotavirus diarrhea

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7128947/

  The Ca2+-dependent endocytosis process represents the most attractive mode of entry and is based on the fact that infectious Rotavirus is endocytosed into the cytoplasm with a very low Ca2+ concentration that leads to a Ca2+ afflux from the vesicles to the cytoplasm. […] A symptomatic infection with Rotavirus stimulates a strong humoral IgG immune response which lasts for the lifetime. […] The pathophysiological mechanisms underlying the fluid losses seen in different types of diarrhea have been debated for decades. […] The demonstration that cholera toxin evoked an increase in intracellular cAMP concentration represented a major breakthrough at the time. […] The experimental evidence for a diminished absorptive capacity of fluid, electrolytes, glucose and amino acids in Rotavirus-infected intestines was reviewed above when describing the morphological and functional effects of the virus.

• #50 Rotavirus infection | Nature Reviews Disease Primers

  https://www.nature.com/articles/nrdp201783

  Rotavirus primarily infects enterocytes and induces diarrhoea through the destruction of absorptive enterocytes (leading to malabsorption), intestinal secretion stimulated by rotavirus non-structural protein 4 and activation of the enteric nervous system. […] In addition, rotavirus infections can lead to antigenaemia (which is associated with more severe manifestations of acute gastroenteritis) and viraemia, and rotavirus can replicate in systemic sites, although this is limited. […] The immune correlates of protection against rotavirus reinfection and recovery from infection are poorly understood, although rotavirus-specific immunoglobulin A has a role in both aspects. […] Rotavirus stimulates release of serotonin (5-HT) from human enterochromaffin cells and activates brain structures involved in nausea and vomiting.

• #51 Rotavirus- An Overview

  https://microbenotes.com/rota-virus/

  Damaged cells may slough into the lumen of the intestine and release large quantities of viruses, which appear in the stool. […] Viral excretion usually lasts from 2 to 12 days in otherwise healthy patients but may be prolonged in those with poor nutrition and immunocompromised patients. […] Immunity to infection requires the presence of antibody, primarily immunoglobulin A (IgA), in the lumen of the gut. […] Antibodies to the VP7 and VP4 neutralize the virus.

• #52 Chapter 19: Rotavirus | Pink Book | CDC

  https://www.cdc.gov/pinkbook/hcp/table-of-contents/chapter-19-rotavirus.html

  The virus enters the body through the mouth. Viral replication occurs in the villous epithelium of the small intestine. Up to two-thirds of children with severe rotavirus gastroenteritis show the presence of rotavirus antigen in serum (antigenemia) and children can have rotavirus RNA detected in serum. […] Infection may result in decreased intestinal absorption of sodium, glucose, and water, and decreased levels of intestinal lactase, alkaline phosphatase, and sucrase activity, and may lead to isotonic diarrhea. […] The immune correlates of protection from rotavirus are not fully understood. Serum and mucosal antibodies against VP7 and VP4 are probably important for protection from disease. Cell-mediated immunity probably plays a role in protection and in recovery from infection.

• #53 Rotaviruses: From Pathogenesis to Disease Control—A Critical Review

  https://www.mdpi.com/1999-4915/14/5/875

  Children experience repeated exposures from birth to old age, though natural and/or vaccine-induced immunity usually makes further infections mild or asymptomatic following natural infection or vaccination. Malnutrition is another factor that potentiates the severity of rotavirus diarrhea by delaying the restoration of the damaged intestinal epithelial barrier and also modifying the intestinal inflammatory responses. In animal models, malnutrition superimposed with RV infection has also been shown to be associated with an enhanced viral shedding and intestinal microbiota translocation to systemic organs due to the compromised intestinal epithelial barrier. […] The determinant of virus virulence is a function of the proteins coded by a subset of the 11 viral genes. Several of the gene segments encode proteins that regulate the multigenicity of the virus virulence. For instance, gene 3 encodes the capping enzyme that facilitates viral RNA replication in infected cells, gene 4, as well as 9, synthesize the outer capsid proteins necessary to initiate infection, gene 10 encodes a nonstructural protein (NSP4), which regulates the internal calcium homeostasis, facilitates virus replication and also functions as an enterotoxin. The NSP1 protein product of gene 5 is associated with host interferon responses inhibition by mediating the breakdown of interferon regulatory factors.

• #54 Rotaviruses: From Pathogenesis to Disease Control—A Critical Review

  https://www.mdpi.com/1999-4915/14/5/875

  Children experience repeated exposures from birth to old age, though natural and/or vaccine-induced immunity usually makes further infections mild or asymptomatic following natural infection or vaccination. Malnutrition is another factor that potentiates the severity of rotavirus diarrhea by delaying the restoration of the damaged intestinal epithelial barrier and also modifying the intestinal inflammatory responses. In animal models, malnutrition superimposed with RV infection has also been shown to be associated with an enhanced viral shedding and intestinal microbiota translocation to systemic organs due to the compromised intestinal epithelial barrier. […] The determinant of virus virulence is a function of the proteins coded by a subset of the 11 viral genes. Several of the gene segments encode proteins that regulate the multigenicity of the virus virulence. For instance, gene 3 encodes the capping enzyme that facilitates viral RNA replication in infected cells, gene 4, as well as 9, synthesize the outer capsid proteins necessary to initiate infection, gene 10 encodes a nonstructural protein (NSP4), which regulates the internal calcium homeostasis, facilitates virus replication and also functions as an enterotoxin. The NSP1 protein product of gene 5 is associated with host interferon responses inhibition by mediating the breakdown of interferon regulatory factors.

• #55 Pathogenesis of Rotavirus diarrhea

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7128947/

  Rotavirus diarrhea is a major cause of infantile gastroenteritis worldwide. This review is mainly devoted to the effects of Rotavirus on intestinal epithelial transport and to the pathophysiological mechanisms proposed to underlie the intestinal fluid secretion caused by the virus. […] This review is devoted to Rotavirus-induced enteric infection, and in particular, to the pathophysiological mechanisms proposed to underlie the intestinal fluid secretion caused by the virus. […] Several of the Rotavirus genes have been associated with their ability to cause disease. The non-structural proteins NSP1, NSP2 and NSP4 are believed to be involved in virulence in mice and the structural proteins vp3 and vp7 in pigs. […] Rotavirus infects the mature enterocytes in the mid and upper part of the villi of the small intestine, which ultimately leads to diarrhea. Current information indicates that Rotavirus attachment and entry into cells constitute a multistep process.

• #56 Genetic Studies of Rotavirus Pathogenesis and Development of Rotavirus Vaccines | National Agricultural Library

  https://www.nal.usda.gov/research-tools/food-safety-research-projects/genetic-studies-rotavirus-pathogenesis-and-development

  Previously, in studies involving a semi-homologous system of gnotobiotic newborn pigs and a virulent porcine rotavirus strain (SB-1A) and an avirulent human rotavirus strain (DS-1) and their reassortants, we demonstrated that: (i) the third (VP3), fourth (VP4), ninth (VP7), or tenth (NSP4) porcine rotavirus gene each play an important independent role in the virulence of rotavirus infection in piglets; and (ii) all four of the porcine rotavirus virulence-associated genes are required for the induction of diarrhea and the shedding of rotavirus by piglets. […] These observations suggested a potential new strategy for attenuation of wild-type human rotaviruses of major epidemiological importance and its application to the development of a safe and effective vaccine. […] Such strains may prove to be important for the development of an optimally effective rotavirus vaccine.

• #57 Rotaviruses: From Pathogenesis to Disease Control—A Critical Review

  https://www.mdpi.com/1999-4915/14/5/875

  Under normalcy, healthy enterocytes secrete lactase into the small intestine that helps in lactose metabolism, but children with rotavirus infection are unable to tolerate milk due to lactase deficiency that can last for several weeks. Such a child may experience recurrence of diarrhea after milk reintroduction into the child’s diet as a result of bacterial fermentation of the lactose in the gut. A third mechanism is based on the stimulation of the enteric nervous system by the viral enterotoxin. The NSP4-mediated increase in intracellular calcium concentration induces the secretion of 5-hydroxytryptamine (5-HT) also called serotonin from enteroendocrine cells in humans. This chemical triggers the activation of enteric nerves that innervate the small intestine, thereby increasing intestinal motility, which is associated with diarrheal onset.

• #58 Rotavirus – PAHO/WHO | Pan American Health Organization

  https://www.paho.org/en/topics/rotavirus

  Although improvements in hygiene, water supply, and wastewater elimination are all measures that can help to reduce severe episodes of diarrhea, comparable incidences of rotavirus disease in developed and developing countries indicate that the disease cannot be controlled exclusively with such measures. […] Four rotavirus vaccines are available on the market and prequalified by WHO, two monovalent, and two pentavalent. Currently, two of them are used in the Region of the Americas. Since 2006, 22 countries and one territory of the Region have introduced this vaccine into their national vaccination schedules.

• #59 Rotavirus vaccine | EBSCO Research Starters

  https://www.ebsco.com/research-starters/consumer-health/rotavirus-vaccine

  The mechanism of action of the rotavirus vaccine depends upon the brand administered. The RotaTeq vaccine is a combination of a bovine strain of the virus that does not cause disease in humans and a component of the human rotavirus that cannot cause active infection. These components are then administered together in an oral dose and elicit an immune response without actually causing the disease, therefore providing protection from future illness. […] The Rotarix brand of the vaccine is derived from a strain of human rotavirus that has been weakened enough to not cause active disease, while still eliciting an immune response from the patient.

• #60 Rotavirus vaccine | EBSCO Research Starters

  https://www.ebsco.com/research-starters/consumer-health/rotavirus-vaccine

  The mechanism of action of the rotavirus vaccine depends upon the brand administered. The RotaTeq vaccine is a combination of a bovine strain of the virus that does not cause disease in humans and a component of the human rotavirus that cannot cause active infection. These components are then administered together in an oral dose and elicit an immune response without actually causing the disease, therefore providing protection from future illness. […] The Rotarix brand of the vaccine is derived from a strain of human rotavirus that has been weakened enough to not cause active disease, while still eliciting an immune response from the patient.

• #61 About Rotavirus | Rotavirus | CDC

  https://www.cdc.gov/rotavirus/about/index.html

  Rotavirus causes common symptoms like watery diarrhea and vomiting, especially in children. […] There is no specific medicine to treat rotavirus infection, but your doctor may recommend medicine to treat the symptoms. […] Rotavirus vaccination is the best way to protect your child from rotavirus disease. […] Since rotavirus disease can cause severe vomiting and diarrhea, it can lead to dehydration (loss of body fluids). […] Severe dehydration may require hospitalization for treatment with intravenous (IV) fluids that patients receive directly through their veins.

• #62

  https://www.healio.com/news/pediatrics/20120331/rotavirus-replication-pathogenesis-and-vaccine-development

  Rotaviruses cause approximately 600,000 deaths worldwide in children younger than five each year. […] Researchers reported in the July 17, 2009, issue of Science that rotavirus vaccination should prevent or lessen the frequency of rotavirus outbreaks, as well as increase the age at which rotavirus presents for the first time in children. […] Understanding the genomic function and makeup of rotavirus proved to be a key factor in the development of rotavirus vaccines. […] „Production of mRNA for protein synthesis is one of the first occurrences when a virus infects a cell.” […] Unlike DNA viruses, a rotavirus conducts its lifecycle in the cytoplasm, never moving into the nucleus. […] „The new resulting reassortant viruses will have picked up some segments from one virus and other segments from the co-infecting virus.”

• #63 About Rotavirus | Rotavirus | CDC

  https://www.cdc.gov/rotavirus/about/index.html

  Rotavirus causes common symptoms like watery diarrhea and vomiting, especially in children. […] There is no specific medicine to treat rotavirus infection, but your doctor may recommend medicine to treat the symptoms. […] Rotavirus vaccination is the best way to protect your child from rotavirus disease. […] Since rotavirus disease can cause severe vomiting and diarrhea, it can lead to dehydration (loss of body fluids). […] Severe dehydration may require hospitalization for treatment with intravenous (IV) fluids that patients receive directly through their veins.

• #64 About Rotavirus | Rotavirus | CDC

  https://www.cdc.gov/rotavirus/about/index.html

  Rotavirus causes common symptoms like watery diarrhea and vomiting, especially in children. […] There is no specific medicine to treat rotavirus infection, but your doctor may recommend medicine to treat the symptoms. […] Rotavirus vaccination is the best way to protect your child from rotavirus disease. […] Since rotavirus disease can cause severe vomiting and diarrhea, it can lead to dehydration (loss of body fluids). […] Severe dehydration may require hospitalization for treatment with intravenous (IV) fluids that patients receive directly through their veins.

• #65

  https://link.springer.com/article/10.1007/s11302-021-09773-y

  Rotavirus (RV) infection causes life-threatening diarrhea, despite only infecting a limited number of intestinal cells. […] However, the mechanisms of RV-induced signaling changes are multifactorial and incompletely understood. […] Here, by combining sophisticated long-term live fluorescent imaging techniques and CRISPR technology in simian- and human-derived cell cultures, the authors show that RV-infected cells signal to surrounding uninfected cells through a purinergic signaling pathway. […] This process is driven by adenosine diphosphate (ADP) release from RV-infected cells and its subsequent interaction with P2Y1 receptors expressed by neighboring cells. […] This mechanism appears to be independent of traditional RV-induced signaling pathways that involve paracrine signaling molecules such as prostaglandin E-2 (PGE2), nitric oxide (NO), or RV enterotoxin nonstructural protein 4 (NSP4).

• #66

  https://link.springer.com/article/10.1007/s11302-021-09773-y

  This study provides a detailed mechanism that explains how RV induces pathology through intercellular purinergic signaling. […] Several drugs targeting P2Y receptors have emerged as candidate therapies for cardiovascular and inflammatory diseases and neurodegeneration. […] The results of this study suggest that these or related compounds could be promising therapeutics that limit RV disease progression. […] Chang-Graham et al.’s work suggests that expanding research in this area to include noninfected neighboring cell populations would improve the mechanistic understanding of disease progression and ultimately, drug development.

• #67 Rotaviruses: From Pathogenesis to Disease Control—A Critical Review

  https://www.mdpi.com/1999-4915/14/5/875

  In the post-attachment stage, the trypsin-like proteases of the gastrointestinal tract proteolytically cleave VP4 spike into VP8 and VP5, a highly ordered conformational change in the capsid proteins and an important event that accelerates viral penetration, thus promoting infectivity. RV infection is largely localized to the intestinal mucosa, although evidence of viral replication has been shown in some distant areas of the body such as lamina propria and regional lymphatics, especially among the immunocompromised individuals. Viral replication at these extraintestinal sites and systemic spread is usually rare in immunologically competent persons. Rotaviral diarrhea is caused by multiple activities of the virus. One mechanism is that the extensive replication of the virus coupled with massive cellular necrosis of the gut epithelium causes villous atrophy, loss of microvilli, severe mononuclear cell infiltration, endoplasmic reticulum and mitochondrial engorgement in enterocytes, and loss of intestinal brush border enzymes such as maltase, sucrase, and lactase. The result of this is nutrients, electrolytes, and fluid malabsorption leading to increased osmotic pressure in the gut lumen and subsequently onset of diarrhea. Reactive crypt-cell hyperplasia following the process may accelerate rates of fluid secretion, thereby increasing the severity of diarrhea.

• #68

  https://link.springer.com/article/10.1007/BF01311255

  The pathogenesis of diarrhea caused by rotavirus infection was studied in miniature swine piglets. […] The present investigation suggests that rotavirus-induced diarrhea is due to virus destruction of enterocytes lining the intestinal villi, thus reducing the mucosal surface area and important digestive enzymes. This destruction leads to an osmotic diarrhea due to nutrient (primarily carbohydrate) malabsorption. […] A possible contributing role of unopposed secretion from the crypt cannot be excluded from this study.

• #69 Pathogenesis of Intestinal and Systemic Rotavirus Infection

  https://pmc.ncbi.nlm.nih.gov/articles/PMC516399/

  Rotavirus infection alters the function of the small intestinal epithelium, resulting in diarrhea. The diarrhea was generally considered to be malabsorptive, secondary to enterocyte destruction. […] The NSP4 enterotoxin activity provides a way to mediate diarrheagenic changes in the absence of significant damage or to mediate changes at uninfected sites. […] Thus, it is clear that rotavirus diarrhea is multifactoral, resulting from the direct effects of virus infection and the indirect effects of infection and the host response. […] The process leading to diarrhea is initiated when rotavirus binds to and infects enterocytes in the small intestine. […] The release of NSP4 from infected cells allows paracrine effects to occur on uninfected cells. […] The secretory component of rotavirus diarrhea appears to be secondary to virus-induced functional changes at the villus epithelium.

• #70 Rotavirus infection pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Rotavirus_infection_pathophysiology

  Proceeding from the virus replication, rotavirus produces the enterotoxins e.g. non structural protein 4 which will have a significant effect in causing the watery diarrhea. […] The infection by the virus destroys the intestinal digestive enzymes like the maltase which is responsible for the carbohydrates digestion. This enzyme destruction increases the fluids in the lumen and causes malabsorption which leads to diarrhea. […] Rotavirus infection is not limited to the intestine only. It can affects the central nervous system causing meningitis.

• #71 Pathogenesis of Intestinal and Systemic Rotavirus Infection

  https://pmc.ncbi.nlm.nih.gov/articles/PMC516399/

  Rotavirus infection alters the function of the small intestinal epithelium, resulting in diarrhea. The diarrhea was generally considered to be malabsorptive, secondary to enterocyte destruction. […] The NSP4 enterotoxin activity provides a way to mediate diarrheagenic changes in the absence of significant damage or to mediate changes at uninfected sites. […] Thus, it is clear that rotavirus diarrhea is multifactoral, resulting from the direct effects of virus infection and the indirect effects of infection and the host response. […] The process leading to diarrhea is initiated when rotavirus binds to and infects enterocytes in the small intestine. […] The release of NSP4 from infected cells allows paracrine effects to occur on uninfected cells. […] The secretory component of rotavirus diarrhea appears to be secondary to virus-induced functional changes at the villus epithelium.

• #72

  https://link.springer.com/article/10.1007/s11302-021-09773-y

  Purinergic signaling through P2Y1 receptors also contributes to diarrhea by stimulating serotonin (5-HT) secretion from RV-infected cells, and small molecule inhibitors of P2Y1 receptors reduced diarrhea severity in infected animals. […] Thus, P2Y1-ADP signaling is a promising target for future RV infection therapies. […] RV induces major alterations to host cell homeostasis which result in the release of potent paracrine signaling molecules including enterotoxin NSP4, PGE2, and NO. […] These paracrine signals are linked to dysregulated serotonergic signaling and enteric modulated secretory function in the gastrointestinal (GI) tract. […] Virally encoded NSP4 is responsible for inducing ICWs in RV-infected cells and is, therefore, the usual suspect for disease onset and progression.

• #73 A new mechanism by which rotavirus makes you sick | BCM

  https://www.bcm.edu/news/a-new-mechanism-by-which-rotavirus-makes-you-sick

  Rotavirus causes gastroenteritis, a condition that includes diarrhea, deficient nutrient absorption and weight loss. […] in this new study researchers at Baylor College of Medicine report a new mechanism by which rotavirus induces diarrhea, interfering with the normal absorption of nutrients in the intestine. […] Rotavirus infection leads to the degradation of DGAT1, an enzyme involved in normal lipid droplet formation in intestinal cells, which in turn reduces the production of key nutrient transporters and other proteins required for normal intestinal nutrient absorption, leading to diarrhea. […] we discovered that rotavirus binds to and breaks down or degrades DGAT1, an enzyme that contributes to the formation of the lipid droplets. […] This led us to think that rotavirus-mediated degradation of DGAT1 could be a mechanism by which the virus induces diarrhea.

• #74 A new mechanism by which rotavirus makes you sick

  https://medicalxpress.com/news/2023-12-mechanism-rotavirus-sick.html

  „But we found a new mechanism by which rotavirus induces diarrhea. Like the children who have a genetic DGAT1 deficiency that causes diarrhea, when rotavirus degrades DGAT1 the result is reduced production of the enzymes that are involved in degrading the food we eat and disruption of the mechanisms that transport nutrients into cells, which leads to diarrhea,” Smith said. […] „It was very surprising that a rotavirus protein that until now was only known to be important for the virus to replicate, also plays a role in causing diarrhea, a major component of the disease. The fact that it’s not a capsid protein or part of the structure that envelops the genetic material of the virus, as we usually would think, tells us that we should not assume that nonstructural proteins do not play roles in causing disease.”

• #75 Rotaviruses: From Pathogenesis to Disease Control—A Critical Review

  https://www.mdpi.com/1999-4915/14/5/875

  Under normalcy, healthy enterocytes secrete lactase into the small intestine that helps in lactose metabolism, but children with rotavirus infection are unable to tolerate milk due to lactase deficiency that can last for several weeks. Such a child may experience recurrence of diarrhea after milk reintroduction into the child’s diet as a result of bacterial fermentation of the lactose in the gut. A third mechanism is based on the stimulation of the enteric nervous system by the viral enterotoxin. The NSP4-mediated increase in intracellular calcium concentration induces the secretion of 5-hydroxytryptamine (5-HT) also called serotonin from enteroendocrine cells in humans. This chemical triggers the activation of enteric nerves that innervate the small intestine, thereby increasing intestinal motility, which is associated with diarrheal onset.

• #76 Pathogenesis of Rotavirus diarrhea

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7128947/

  One of the non-structural proteins of Rotavirus, NSP4, is a transmembrane, endoplasmatic reticulum-specific glycoprotein. […] The main body of experiments with NSP4 residues 114135 suggest that it may function as a virus enterotoxin at least in mice. […] Several observations made during Rotavirus enteritis in neonatal mice suggest that the secretory response is in part explained by an activation of the ENS.

• #77 Pathogenesis of Intestinal and Systemic Rotavirus Infection

  https://pmc.ncbi.nlm.nih.gov/articles/PMC516399/

  The central players in secretion appear to be NSP4 and the ENS. […] The numerous clinical reports of rotavirus at systemic sites and work with mice that showed systemic spread prompted a systematic search for evidence of widespread rotavirus viremia in children and animal model systems. […] The studies reviewed here indicate that we have made significant progress in understanding the molecular basis for rotavirus intestinal pathogenesis and spread to peripheral sites.

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