Enteric viral infections, including rotaviruses and noroviruses, remain one of the greatest public health challenges worldwide. In addition, the intestinal mucosa is a critical site for early control of HIV replication and dissemination. Understanding the cellular and molecular mechanisms through which the mucosal immune system recognizes and successfully eradicates enteric viral pathogens is critical for designing better oral vaccines. However, fundamental questions remain unanswered regarding (i) where virus-specific effector and memory T cell responses are primed in the intestinal mucosa;(ii) how the innate immune system recognizes enteric viruses;and (iii) how alterations in intestinal microbiota influence anti-viral immune responses. In preliminary studies, we established mouse Norovirus (MNV) as a model of natural enteric viral infection in humans and generated new tools to track MNV-specific T cell responses. Our preliminary data support the hypothesis that intestinal epithelial cells (lECs) and intestinal commensal bacteria can promote virus-specific T cell responses and host protective immunity following MNV infection. Based on these findings, three fundamental questions will be tested in this proposal (i) Where are MNV- specific T cell responses primed and what regulates MNV-specific memory T cell responses? (ii) How do innate immune cells recognize and respond to MNV infection in the gut? (iii) How do commensal microbial communities influence innate and adaptive immunity to MNV? Collectively, these studies will interrogate the influence of the innate immune response and environmental pathways on the priming and maintenance of MNV-specific T cell responses and host protective immunity in the intestine. Understanding the mechanisms through which the mucosal immune system successfully recognizes enteric viral pathogens and mounts a protective innate and adaptive immune response will be critical for the design of a new generation of successful immuno-modulatory drugs and oral vaccines.

Public Health Relevance

Intestinal viral infections are a major worldwide cause of gastroenteritis and diarrhea leading to significant morbidity and mortality. In addition, the intestinal mucosa is a critical site for early control of HIV replication and dissemination. However, we understand relatively little about the development anti-viral innate and adaptive immunity following enteric viral infection. This proposal will address these gaps in knowledge.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZAI1-WFD-I (M2))
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Rothermel, Annette L
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University of Pennsylvania
Schools of Medicine
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Moriyama, Saya; Brestoff, Jonathan R; Flamar, Anne-Laure et al. (2018) ?2-adrenergic receptor-mediated negative regulation of group 2 innate lymphoid cell responses. Science 359:1056-1061
Joseph, Ann M; Monticelli, Laurel A; Sonnenberg, Gregory F (2018) Metabolic regulation of innate and adaptive lymphocyte effector responses. Immunol Rev 286:137-147
Veiga-Fernandes, Henrique; Artis, David (2018) Neuronal-immune system cross-talk in homeostasis. Science 359:1465-1466
Meisel, Jacquelyn S; Sfyroera, Georgia; Bartow-McKenney, Casey et al. (2018) Commensal microbiota modulate gene expression in the skin. Microbiome 6:20
Zhou, Lei; Sonnenberg, Gregory F (2018) Essential immunologic orchestrators of intestinal homeostasis. Sci Immunol 3:
Chu, Coco; Moriyama, Saya; Li, Zhi et al. (2018) Anti-microbial Functions of Group 3 Innate Lymphoid Cells in Gut-Associated Lymphoid Tissues Are Regulated by G-Protein-Coupled Receptor 183. Cell Rep 23:3750-3758
Blander, J Magarian; Longman, Randy S; Iliev, Iliyan D et al. (2017) Regulation of inflammation by microbiota interactions with the host. Nat Immunol 18:851-860
Kurachi, Makoto; Kurachi, Junko; Chen, Zeyu et al. (2017) Optimized retroviral transduction of mouse T cells for in vivo assessment of gene function. Nat Protoc 12:1980-1998
Wallrapp, Antonia; Riesenfeld, Samantha J; Burkett, Patrick R et al. (2017) The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation. Nature 549:351-356
Tomov, Vesselin T; Palko, Olesya; Lau, Chi Wai et al. (2017) Differentiation and Protective Capacity of Virus-Specific CD8+ T Cells Suggest Murine Norovirus Persistence in an Immune-Privileged Enteric Niche. Immunity 47:723-738.e5

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