Viruses transmitted by the fecal-oral route are among the most common human infections, but little is known about factors that influence transmission and viral replication in the intestine. The gastrointestinal tract is a complex environment and enteric viruses encounter a vast microbial community. Intestinal bacteria promote replication and pathogenesis of enteric viruses in mice, including poliovirus, reovirus, mouse mammary tumor virus, and norovirus. Thus, unrelated viruses from four families benefit from intestinal bacteria, highlighting the importance of understanding virus-microbiota interactions. Microbiota promote replication of enteric viruses through multiple mechanisms, including direct interactions with viral particles that aid attachment and stability, and indirect modulation of the host innate immune response. Although poliovirus and coxsackievirus B3 (CVB3) are two closely related viruses in the Picornaviridae family, our data suggest that microbiota enhance their infection through distinct mechanisms. While inhibition of poliovirus replication requires a potent cocktail of four antibiotics, CVB3 replication is inhibited by much more subtle antibiotic regimens. These results suggest that CVB3 is more reliant on microbiota than poliovirus and that a specific subset of bacteria may be required for efficient CVB3 infection. Bacteria in the colon ferment dietary fiber to produce short-chain fatty acids (SCFAs) including acetate, propionate, and butyrate. SCFAs are among the most abundant molecules in the distal gastrointestinal tract and influence intestinal metabolism and gene expression in ways that could impact enteric virus replication. Recently, we determined that a single bacterial metabolite, butyrate, is sufficient to promote CVB3 replication in microbiota-depleted mice. Our central hypothesis is that bacteria-derived SCFAs promote enteric virus replication by altering host gene expression and intestinal homeostasis. In this work we will 1. Examine the specificity of SCFA-mediated effects on enteric virus replication and 2. Examine how SCFA-mediated changes in host gene expression affect enteric virus replication. Overall, our goal is to use the power of model viruses to understand mechanisms by which bacteria promote enteric virus infection.

Public Health Relevance

Mammalian enteric viruses are important and common human infections, but factors that control their replication in the intestine are unclear. This work will examine how metabolites from intestinal bacteria influence enteric virus infection and disease in mice.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Special Emphasis Panel (ZRG1)
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Park, Eun-Chung
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University of Texas Sw Medical Center Dallas
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