Abstract PR03: Functional characterization of the enteric animal virome as mediator of host health
Authors: Dallari Simone , Heaney Thomas , Rosas-Villegas Adriana , Cadwell Ken 
Published: December 2020

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 cause subclinical infections, and indeed are often detected in asymptomatic individuals. The consequences of harboring these viruses are unclear. We recently demonstrated that norovirus mono-colonization promotes the development of the intestinal architecture and the mucosal immune system of germ-free mice in a manner similar to symbiotic bacteria and can protect against models of chemical and microbial injury. It is unclear whether this symbiotic virus-host relationship is a unique feature of murine norovirus strain CR6 colonization. Here, we examined the extent to which members of the eukaryotic enteric virome contribute to the state of the host health. Examination of 10 enteric DNA and RNA viruses representing 6 viral families capable of spreading through the fecal-oral route revealed that many establish a prolonged infection, which often is not limited to the intestinal tissues, in the absence of visible disease after oral inoculation. Further histologic analysis of the small intestinal and colonic tissues confirmed no pathogenic effects on the intestinal tissues. To evaluate the direct impact of asymptomatic viral infections independently from the bacterial microbiome, we performed RNA-seq on intestinal tissues and a comprehensive flow cytometry analysis of intestinal and extraintestinal organs, assessing over 20 immune cell subsets and their cytokine production capacity, following viral mono-colonization of germ-free mice. We found profound effects exerted by the enteric viruses on the immune system in all the tissues tested. In addition to confirming anticipated consequences of viral infection such as expansions of Th1 cells and effector memory T cells, we identified novel virus-specific responses, such as norovirus-induced expansion of type 1 regulatory T cells and parvovirus-mediated induction of regulatory T cells. Interestingly, intestinal T cells and innate lymphoid cells from almost all the virome-colonized mice were more predisposed towards the production of proinflammatory Th1 cytokines, such as IFNγ, and of Il22. An increase in the IL22 signature was also detected in the intestinal transcriptome of virome-colonized mice, suggesting that the virome members support the production of this cytokine already at the steady-state level. Of note, only a few viruses were inducing a type I interferon signature in the tissues, suggesting that pathways other than type I interferon mediate the virome effects on the host. Taken together, these data demonstrate that multiple members of the enteric virome can contribute to the development and function of the mucosal immune system.
This abstract is also being presented as Poster A13.
Citation Format: Simone Dallari, Thomas Heaney, Adriana Rosas-Villegas, Ken Cadwell. Functional characterization of the enteric animal virome as mediator of host health [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr PR03.