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fredag 31 mars 2017

Virusripuleista: ROTAVIRUS

(Muistiin 31.3. 2017, käännettävä myöhemmin)
 http://abdominalkey.com/viral-diarrhea/
Rotavirus tuhoaa  enterosyyttejä. Vähentää suolen toimivaa pintaa.Nukkakärki tuhoutuu ja kryptaalue kompensatorisesti proliferoituu. Monimuotoinen imeyttämisvaje sekä joniripuli, koleramaineen nesteen menetys.

Viral Diarrhea

Established
Probable
Possible in selected children
Rotavirus
Torovirus
HIV
Norovirus
Aichi virus enterovirus 22
Cytomegalovirus
Adenovirus
 
Epstein–Barr virus picobirnavirus
Astrovirus
  
The viruses most frequently responsible for acute gastroenteritis in children belong to four distinct families: rotaviruses, caliciviruses, astroviruses, and enteric adenoviruses. Rotavirus and norovirus are the two leading agents of acute diarrhea. Other viruses, such as toroviruses, picornaviruses (the Aichi virus), and enterovirus 22, play a minor epidemiological role. Finally, selected viruses induce diarrhea only in children at risk. These include cytomegalovirus, Epstein–Barr virus, picobirnaviruses, and HIV.

Pathophysiology of Viral Diarrhea

In the classic and simple view, the pathogenesis of diarrhea may be divided into osmotic and secretory. Viral diarrhea was originally believed to be the consequence of endoluminal fluid accumulation osmotically driven by non-absorbed nutrients due to cell invasion and epithelial destruction by enteropathogenic agents. It is now known that several mechanisms are responsible for diarrhea, depending on the specific agents and the host features. In addition, selected viruses have multiple virulence pathways that act synergistically to induce diarrhea.

The mechanisms of diarrhea induced by group A rotaviruses have been extensively investigated and provide a paradigm of the pathophysiology of viral diarrhea [2022]. Rotavirus has both a tissue- and a cell-specific tropisms, and it infects the mature enterocyte of the small intestine. The first step is virus binding to specific receptors located on the cell surface, the GM1 ganglioside. However, different rotavirus strains bind in either a sialic-acid-dependent or sialic-acid-independent fashion. Most rotaviruses, including all human strains, infect polarized enterocytes through both the apical and the basolateral side, in a sialic-acid-independent manner, suggesting the presence of different receptors. The early stages of rotavirus binding involve the viral protein (VP4) spike attachment and cleavage. After binding, rotavirus enters into the cell by a multistep process that requires both VP7 and VP4 proteins. Infection of the villous enterocytes leads to cell lysis, compromising nutrient absorption and driving fluid into the intestinal lumen through an osmotic mechanism. However, the destruction of villus-tip cells induces a compensatory proliferation of crypt cells. These immature enterocytes physiologically maintain a secretive tone, thus contributing to diarrhea with ion secretion, as the result of the imbalance between absorptive villous and secretory crypt cells. Thus, the cytopathic effect of rotavirus results in both osmotic and secretory diarrhea . Histological changes induced by rotavirus infection occur within 24 h of infection in animal models .

The enteric nervous system may also play a direct role in inducing fluid secretion, similar to that induced by cholera toxin and other intestinal secretagogues. The molecular mechanisms of fluid secretion have also been investigated. Rotavirus induces an increase in intracellular calcium levels, which is responsible for the disassembly of microvillar F-actin, the perturbation of cellular protein trafficking, the damage of tight junction, with a disruption of cell–cell interaction and cytolysis .

In children with rotavirus infection, the onset of diarrhea is abrupt and occurs in the absence of histological changes, suggesting that in the initial phase of the infection a secretory pathway is responsible for diarrhea. The identification of the nonstructural protein (NSP4), an enterotoxin produced by rotavirus, responsible for fluid secretion but not for epithelial damage may explain this phenomenon. NSP4 is a multifunctional virulence factor (VF), as it possesses the following features (Fig. 14.1): It is released from infected cells and enters the cells through a specific receptor causing calcium-dependent chloride secretion. NSP4 also alters plasma membrane permeability and is cytotoxic. NSP4 is the only rotavirus gene product capable of eliciting intracellular calcium mobilization. NSP4 further contributes to diarrheal pathogenesis by directly altering enterocyte actin distribution and paracellular permeability. Finally, NSP4 plays a role in the inhibition of the Na+-dependent glucose transporter (SGLT-1). Glucose absorption as well as disaccharidase activities are impaired in rotavirus enteritis, whereas the Na/amino acid co-transporters are not involved .
Fig. 14.1
Combined effects by NSP4 in the pathophysiology of rotavirus diarrhea. Rotavirus infects epithelial cells of the small intestine, replicates, and induces cell lysis. NSP4 is released by infected cells and functions as a Ca2+-dependent enterotoxin triggering Cl secretion. It decreases fluid and electrolyte transport by inhibiting Na–glucose symport SGLT1 and, possibly Na–K adenosine triphosphatase (ATPase). It also impairs disaccharidase expression. Furthermore, rotavirus and/or NSP4 may diffuse underneath the intestinal epithelium activating secretory reflexes in the enteric nervous system. Late during the infection, an inflammatory response in the lamina propria may be detected, and the production of inflammatory substances and cytokines may further contribute to the increase of intestinal permeability and diarrhea. NSP4 nonstructural protein, SGLT-1 Na+-dependent glucose transporter, NO nitrous oxide. (Reprinted with permission from Ref. [19], 2004, Fig. 9.3, p. 131)
Rotavirus diarrhea may also have an inflammatory component. The induction of cytokines is important in developing an inflammatory and immune response, especially in intestinal infection caused by bacteria. In rotavirus infection, limited inflammation is detected by histological studies, suggesting that cytokines are effective in inducing a host immune response to rotavirus diarrhea. However, it has been shown that rotavirus-infected enterocytes activate nuclear factor kappa B (NF-κB) and the production of chemokines interleukin (IL)-8, Rantes, and growth related oncogene (GRO)-a, of interferon (IFN)-α, and of granulocyte/macrophage–colony-stimulating factor (GM-CSF). Recent evidence suggests that rotavirus-induced diarrhea may be also associated with an increase of intestinal motility through the stimulation of myenteric nerve plexus [23].
In conclusion, the primary target of rotavirus is the enterocyte, which is induced to secrete fluids and electrolytes and is subsequently destroyed. On the other hand, the enterocyte acts as a sensor to the mucosa with the production of viral and endogenous factors and the activation of other cell types including neurons. Thus, rotavirus-induced diarrhea is a multistep and multifactorial event, in which fluid secretion and cell damage are observed in a precise sequence, as shown in an intestinal cell line-based experimental model [24] (Fig. 14.2). A summary of the multiple mechanisms involved in the rotavirus–intestine interaction is provided in Table 14.2 .
Fig. 14.2
Biphasic effect of rotavirus in Caco-2 cells. Rotavirus induces a biphasic response, in an in vitro model of infection in Caco-2 enterocytes mounted in Ussing chambers. An early secretion is evident in the first few hours of infection, with a peak at 2-h postinfection, as shown by the increase in short circuit current (Isc, µA). Subsequently, rotavirus exerts a cytotoxic effect with a loss of tissue integrity, as demonstrated by the fall of transepithelial resistance (TER) (Ohm/cm2) which is evident at 24-h postinfection. The results suggest that rotavirus diarrhea is initially the result of an early secretory mechanism and of a subsequent osmotic pathway, due to cell damage and loss of functional absorptive surface, leading to nutrient malabsorption. (Reprinted with permission from Ref. [19]. Reprinted from Ref. [24], by Permission of Oxford University Press)
Table 14.2
Mechanisms involved in rotavirus-induced diarrhea
Mechanism
Effect
Enterocyte damage
Nutrient malabsorption/osmotic diarrhea
Crypt cell proliferation
Ion and water secretion/secretory diarrhea
NSP4 production
Increase in intracellular calcium, chloride secretion/secretory diarrhea
NSP4 inhibition of SGLT-1
Glucose malabsorption/osmotic diarrhea
Neuromediated vascular ischemia
Secretory diarrhea induced by neurotransmitter release
Inflammation
NF-kB, IL-8, Rantes release/osmotic, and secretory diarrhea
Stimulation of myenteric nerve plexus
Increase in intestinal motility
NSP4 nonstructural protein, NF-κB nuclear factor kappa B, IL interleukin, SGLT-1 Na+ -dependent glucose transporter



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