Rotavirus Induced Diarrhea
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Rotavirus Induced Diarrhea
Acute gastroenteritis is among the most common illnesses of humankind, and its associated morbidity and mortality are greatest among those at the extremes of age, children and the elderly. In developing countries, gastroenteritis is a common cause of death in children that can be linked to a wide variety of pathogens. Much of the gastroenteritis in children is caused by viruses belonging to four distinct families-Rotaviruses, Caliciviruses, Astroviruses and Adenoviruses. Viral gastroenteritis occurs with two epidemiologic patterns, diarrhea that is endemic in children and outbreaks that affect people of all ages. Viral diarrhea in children is caused by Group-A Rotavirus and the illness affects all children worldwide in the first few years of life regardless of their level of hygiene, quality of water, food or sanitation, or type of behavior (Ref.1). Rotaviruses are members of the Reoviridae family and contain 11 dsRNA (double-stranded RNA) segments inside a TLP (Triple Layered Protein) capsid. The segmented double-stranded RNA genome encodes six structural proteins (VP1, VP2, VP3, VP4, VP6, and VP7) and six nonstructural proteins (NSP1 to NSP6). VP4 and VP7 are capsid proteins found on the outer proteinaceous layer of the virus. VP4 is important for viral adsorption and penetration into epithelial cells, and VP7 may also play a role in these functions. VP3 and VP6 encode proteins required for RNA transcription and correct viral structure (Ref.2).

Rotaviruses infect and replicate within the mature epithelial cells at the apex of the villus, and viral progeny exit the cell from the luminal membrane by a process of transcytosis. The early events in infection are mediated by virus-epithelial cell interactions during which at least three contacts between the virus and cell receptors occur. Different rotavirus strains display different requirements to infect cells. Some strains depend on the presence of sialic acid on the cell surface. These first two interactions are mediated by the virus spike protein VP4. After attaching to the cell, all three strains interact with Integrin AlphaVBeta3 and protein HSP70 (70-kD Heat-shock protein). These molecules which serve as rotavirus receptors is found associated with cholesterol and glycosphingolipid-enriched lipid micro domains, and disorganization of these domains greatly inhibits rotavirus infectivity (Ref.3). Diarrhea may be caused by several mechanisms including (i) malabsorption that occurs secondary to the destruction of enterocytes, (ii) villus ischemia and activation of the ENS (Enteric Nervous System) that may be evoked by release of a vasoactive agent from infected epithelial cells in the absence of significant pathologic lesions or enterocyte damage, and (iii) intestinal secretion stimulated by the intracellular or extracellular action of NSP4 (Ref.4). During the first cycle of rotavirus replication in mucosal epithelial cells, the synthesis of rotaviral proteins in the cell cytoplasm leads to an increase in the plasma-membrane permeability to Ca2+, to activation of regulatory mechanisms and to an increase in the concentration of Ca2+ in the endoplasmic reticulum through SERCA (Sarco- and Endoplasmic Reticulum Ca2+ ATPase). In the extracellular medium, Ca2+ stabilizes the structure of the viral capsid but the increased concentration of cytosolic Ca2+ in infected cells promotes the activation of Ca2+ dependent enzyme, which in turn induces cell lysis and the release of viral proteins and viral progeny (Ref.5). NSP4 also act as a viral enterotoxin to induce secretory diarrhea through Ca2+-dependent secretion by intestinal cells, Ca2+-dependent secretion of peptides and amines to stimulate the ENS, or by further activation of epithelial-cell chloride (Cl-) secretion by the ENS. NSP4 increases [Ca2+]i and this elevation in [Ca2+]i is not due to an increased influx of extracellular Ca2+ but due to result from the increase in Ca2+ efflux from the endoplasmic reticulum through a PLC (Phospholipase-C)-dependent mechanism. Exogenous NSP4 induce both Ca2+ release from intracellular stores and plasmalemma Ca2+ influx, through receptor-mediated PLC activation and IP3 (Inositol 1,4,5-triphosphate) production (Ref.6). In parallel, released virus infects downstream absorptive cells. This leads to a massive cell death and, as a consequence, reduction of the absorptive surface of the intestinal epithelium and an osmotic component of diarrhea.

Rotaviruses are the most important cause of severe, often life-threatening gastroenteritis in infants and children under 2 years of age. These viruses are ubiquitous in nature and are also responsible for a significant proportion of neonatal diarrhea illness in domestic animals, particularly in bovine and porcine species. Rotavirus gastroenteritis usually starts with fever, an upset stomach, and vomiting, followed by diarrhea. The watery diarrhea can be mild to severe and generally lasts for 3 to 9 days. Severe diarrhea can lead to a dangerous depletion of body fluids called dehydration, which can result in death if untreated (Ref.7). Virtually all children become infected with rotavirus in the first 3 to 5 years of life, but severe diarrhea and dehydration occur mainly among children aged 3 to 35 months. There are a number of different strains of rotavirus than cause gastroenteritis in humans; 4 strains are common in the United States. Children get rotavirus infection several times, and each new infection tends to be less serious than the previous infection. There is no effective way to completely eliminate rotavirus infection or its transmission. Washing with soaps or cleansers does not kill the virus, but careful hand washing will help prevent spread of rotavirus.