Functional characterization of the enteric animal virome

Abstract

Abstract The enteric virome includes viruses that infect eukaryotic cells in the gut and is one constituent of the mammalian microbiome. Although best known for causing acute diarrheal disease, many of these viruses are detected in asymptomatic individuals. The immune consequence of harboring these viruses is unclear. We recently demonstrated that norovirus infection promotes the development of the mucosal immune system in mice in a manner similar to symbiotic bacteria, and can protect against models of chemical and microbial injury. These results are reminiscent of findings from the microbiome field demonstrating that intestinal colonization by individual bacterial species directs the differentiation of the immune system. Here, we examined the extent to which the eukaryotic enteric virome contributes to the state of the host immune system. Examination of 10 enteric DNA and RNA viruses, representing 6 viral families, revealed that many establish prolonged infection in the absence of disease. To evaluate the immunological impact of these viral infections that occurs independently of other members of the microbiome, we performed a comprehensive flow cytometry analysis of several organs following infection of germ-free mice that assessed over 20 immune cell subsets and their capacity for cytokine production. We found profound effects of enteric viral infection in all the tissues tested, showing strain-specific responses, such as norovirus-induced expansion of type 1 regulatory T cells, and commonly shared ones, such as the increased potential of colonic T cells to produce Il-22. Taken together, these data demonstrate that enteric virome members contribute to the immune status of the host.