Rotavirus Disease Mechanisms Diarrhea, Vomiting and Inflammation : How and Why

Abstract

Rotavirus infections cause diarrhea and vomiting that can lead to severe dehydration. Despite extensive tissue damage and cell death, the inflammatory response is very limited. The focus of this thesis was to study pathophysiological mechanisms behind diarrhea and vomiting during rotavirus infection and also to investigate the mechanism behind the limited inflammatory response. An important discovery in this thesis was that rotavirus infection and the rotavirus toxin NSP4 stimulate release of the neurotransmitter serotonin from intestinal sensory enterochromaffin cells, in vitro and ex vivo. Interestingly, serotonin is known to be a mediator of both diarrhea and vomiting. Moreover, mice pups infected with rotavirus responded with central nervous system (CNS) activation in brain structures associated with vomiting, thus indicating a cross-talk between the gut and brain in rotavirus disease. Our finding that rotavirus infection activates the CNS led us to address the hypothesis that rotavirus infection not only activates the vagus nerve to stimulate vomiting, but also suppresses the inflammatory response via the cholinergic anti-inflammatory pathway, both of which are mediated by activated vagal afferent nerve signals into the brain stem. We found that mice lacking an intact vagus nerve, and mice lacking the α7 nicotine acetylcholine receptor (nAChR), being involved in cytokine suppression from macrophages, responded with a higher inflammatory response. Moreover, stimulated cytokine release from macrophages, by the rotavirus toxin NSP4, could be attenuated by nicotine, an agonist of the α7 nAChR. Thus, it seems most reasonable that the cholinergic anti-inflammatory pathway contributes to the limited inflammatory response during rotavirus infection. Moreover, rotavirus-infected mice displayed increased intestinal motility at the onset of diarrhea, which was not associated with increased intestinal permeability. The increased motility and diarrhea in infant mice could be attenuated by drugs acting on the enteric nervous system, indicating the importance and contribution of nerves in the rotavirus mediated disease. In conclusion, this thesis provides further insight into the pathophysiology of diarrhea and describe for the first time how rotavirus and host cross-talk to induce the vomiting reflex and limit inflammation. Results from these studies strongly support our hypothesis that serotonin and activation of the enteric nervous system and CNS contributes to diarrhea, vomiting and suppression of the inflammatory response in rotavirus disease

Prevalence and Factors Associated with Rotavirus Infection among Vaccinated Children Hospitalized for Acute Diarrhea in Mwanza City, Tanzania: A Cross Sectional Study

“…This study showed that vomiting was significantly associated with Rotavirus infection, which is similar to the previous studies done in pre-vaccine era in rural Western Kenya, Northwestern Angola, Accra, Ghana, urban Bangladesh and which ultimately induces vomiting reflex, nausea and vomiting [18]. This study has found that vaccinated children indwelling with three or more fellow children in the same house are significantly more likely to acquire Rotavirus infection compared to those indwelling with less than three fellow children.…”

Rotavirus in Calves and Its Zoonotic Importance

“…Although early studies implicated VP7 in the cell entry process, subsequent studies increasingly have indicated that VP4 is the major player in Veterinary Medicine International this process. VP4 is susceptible to proteolysis and viral infectivity is increased several folds when VP4 is proteolytically cleaved and facilitates virus entry into cells [22]. During proteolysis, VP4 is cleaved into VP8 * (amino acids 1 to 247) and VP5 * (amino acids 248 to 776), and the cleavage products remain associated with the virion [30].…”

“…Finally, the higher intraenterocyte calcium concentration causes enterocytes to die by oncosis. e rate of death of the mature villous tip enterocytes exceeds the rate of growth of immature enterocytes that are regenerated from the stem cells in the crypt, causing villous blunting and thus malabsorption [22]. Infection resolves both as the virus runs Veterinary Medicine International out of susceptible mature enterocytes and an immune response is generated [69].…”

Prevalence and Molecular Detection of Rotavirus in Children in Ramadi City-Iraq

“…Infected children may also have a cough and runny nose. 8,9,10,11,12,13 Generally, reinfections are common in Rotavirus disease. 14 Immunity develops with each infection, so subsequent infections are less severe; adults are rarely affected.…”