Decoding mechanisms of diarrhea induction by enteric viruses

Infectious diarrhea kills more children each day than AIDS, malaria, and measles combined [1].In humans, the leading causes of virally induced diarrhea include rotavirus, norovirus, sapovirus, astrovirus, adenovirus, and poliovirus, prior to a global vaccination program, all of which pose significant risks particularly to young children and the immunocompromised population [1].Here, we summarize shared and distinct mechanisms employed by these viruses to cause diarrheal diseases.This brief review aims not only to serve and inform clinical and research communities but also paves the path for developing therapies and countermeasures to mitigate the impact of the diarrhea caused by these pathogens.DisruptionAU : Pleaseconfirmthatallheadinglevelsarerepresentedcorrectly: of intestinal homeostasis Rotavirus and norovirus are both capable of disrupting intestinal epithelial barriers but through different mechanisms.Rotavirus mainly infects mature non-proliferative enterocytes at the tip of villi in the small intestine and causes structural changes such as villus blunting in humans [2].Breakdown of barrier function does not seem to be observed in mouse models of rotavirus infection, which could be due to increased stem cell division or neurotropic factor production [3,4].This selective cell tropism towards mature absorptive enterocytes can lead to disruptions in normal intestinal physiology.Rotavirus infection also depresses the function of key apical transport proteins, such as sodium-D-glucose, sodium-hydrogen exchanger 3, and cystic fibrosis transmembrane conductance regulator, which are crucial for sodium and chloride transport in the small intestine [5].Additionally, diacylglycerol O-acyltransferase 1 (DGAT1) is degraded in rotavirus antigen positive cells [5].This degradation disrupts the localization of key ion transporters and reduces the expression of various intestinal proteins, leading to impaired nutrient absorption and malabsorptive noninflammatory diarrhea [5].Human norovirus-induced diarrhea is associated with significant histopathological changes within the small intestine, despite minimal visible damage or inflammation.Key changes include the broadening and blunting of intestinal villi, vacuolization of epithelial cells, and hyperplasia of crypt cells [6].These alterations, along with observed lacteal dilation, suggest impaired fat absorption and contribute to the malabsorptive aspect of diarrhea.Because human norovirus does not infect mice due to host range restriction, many of the disease studies stem from experimental murine noroviruses, whose cell tropism is strain dependent and largely found in subepithelial cells of the small intestinal gut-associated lymphoid tissue and lamina propria.Furthermore, the involvement of lymphocytes indicates a complex interplay where these cells help control viral replication but also exacerbate disease severity, highlighting a dual role in the pathogenesis of murine norovirus diarrhea [7].Interestingly, murine norovirus infection only induces diarrhea in neonatal but not adult mice [7].