Regulation of Interferon-Lambda Signaling by Commensal Bacteria and Norovirus

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PROJECT SUMMARY/ABSTRACT Candidate: During my training, I have been highly motivated to understand the host response to the environment, especially to pathogenic and commensal bacteria and viruses. This motivation has contributed to a successful record of publications, representing advances in the understanding of how the immune system responds to and is regulated by systemic and mucosal infections. My long-term research goals center on defining the mechanisms by which infectious diseases are affected by host genetics and the microbiota. Research Career Development Plan: As I complete my highly successful research fellowship with my mentor Dr. Virgin, a nationally-recognized expert in host:pathogen interactions, I will utilize educational and research resources at Washington University to strengthen my career development. I will pursue further training in bioinformatic analysis and intestinal imaging, and prepare to transition to a tenure-track faculty position by planning for the management and mentorship responsibilities of an independent investigator. Research Project: Noroviruses are highly infectious pathogens that cause acute gastroenteritis and persistent viral shedding in humans. A proviral role for commensal bacteria in intestinal infection by murine norovirus (MNoV), a small animal model for norovirus pathogenesis, was recently uncovered. Interferon- lambda (IFN-λ) is an innate immune cytokine which is potently antiviral against MNoV, and is important for regulating this bacteria-MNoV interaction. However, the interactions between commensal bacteria, MNoV, and endogenous IFN-λ remain unclear. This project proposes to interrogate the role of MNoV and commensal bacteria in IFN-λ induction. Commensal microbes induce IFN-stimulated genes (ISGs) in the intestinal epithelium, in a manner dependent on the presence of the IFN-λ-receptor Ifnlr1. Ifnlr1 expression on epithelial cells also regulates MNoV shedding and clearance. While epithelial cells respond to IFN-λ in the intestine, the host cell type producing IFN-λ in response to commensal bacteria or MNoV remains unknown. Studies to define this IFN-λ source will clarify the interaction between this viral pathogen, the microbiota, and the host innate immune system. Bacterial and viral products, acting through pattern-recognition receptors, stimulate production of IFNs. However, the pathways regulating induction of IFN-λ by MNoV and commensal bacteria are unknown. Understanding the regulation of endogenous IFN-λ is needed to uncover how persistent NoV evades the innate immune system, possibly via cloaking by commensal bacteria. These studies may reveal novel vaccination strategies or therapeutic interventions for norovirus infection, which will likely be broadly relevant to other mucosal viruses. IFN-λ is a critical modulator in the relationship between microbes and the host intestine, and study of this molecule will inform our approach to pathogen infection at mucosal surfaces. Completion of these studies will lay the scientific groundwork for both future R01 applications and for a successful career studying the interactions of viral pathogens, the microbiome and the host immune system.