Studies of pathogenesis, innate immunity and therapeutics of human enteric viruses in gnotobiotic pigs

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Virginia Tech


Norovirus and rotavirus are the most common viral causes of acute gastroenteritis among all age groups and in children under 5 years of age, respectively. Understanding the pathogenesis of the virus and correlates of protective immunity is fundamental to developing effective prevention and treatment strategies. Gnotobiotic (Gn) pigs are an attractive animal model for studying enteric viruses due to their similarities to humans, particularly in regards to the immune system and gastrointestinal anatomy and physiology. Here, to establish a reliable Gn pig model of human norovirus (HuNoV) infection and disease, we determined the median infectious dose (ID50) of a GII.4 2006b variant in pigs. We also evaluated the effects of age and administration of the cholesterol-lowering drug simvastatin on susceptibility to NoV infection. In neonatal pigs (4-5 days of age, the ID50 was determined to be 2.74 x 103 viral RNA copies. The ID50 was increased in 33-34 day old pigs (6.43 x 104), but decreased to <2.74 x 103 following simvastatin treatment in the same age group. Overall, the development of diarrhea, fecal virus shedding and small intestinal cytopathological changes confirmed the usefulness of the Gn pig as an appropriate animal model for studying HuNoVs. We also utilized the well-established Gn pig model of human rotavirus (HRV) infection and disease to evaluate adjunctive treatment options for HRV-induced diarrhea. We demonstrated that the anti-secretory drug racecadotril was capable of diminishing clinical signs of HRV infection and shortening duration of illness. Reduced dehydration in the racecadotril-treated pigs was evident by the significant gain in body weight compared to controls during the course of the study. We also determined that a high dose of the probiotic Lactobacillus acidophilus NCFM (LA) was able to reduce RV diarrhea severity and duration compared to a low dose. The difference in therapeutic potential was attributed to divergent effects in innate immunity pre- and post-challenge. High dose of LA (HiLA) induced an anti-inflammatory dendritic cell (DC) profile, characterized primarily by upregulation of TLR2 expression and production of cytokine IL-10. Conversely, low dose of LA (LoLA) upregulated TLR3 and TLR9 and increased secretion of cytokine IL-6. Additionally, HiLA induced both IFN-alpha and TNF-alpha responses in DCs, but LoLA was only able to increase the frequency of TNF-alpha-producing DCs. These results provide further support of Gn pigs as a highly applicable animal model for studying pathogenesis, innate immunity and therapeutics of human enteric viruses.



human rotavirus, human norovirus, gnotobiotic pigs, pathogenesis, dendritic cells, anti-diarrheal drugs