Exploring the role of T cells in protection from respiratory virus transmission

PROJECT SUMMARY / ABSTRACT Respiratory viruses remain a major threat to human health, and the development of novel approaches to promote durable protective immunity against both severe disease and viral transmission are sorely needed. Respiratory virus infection and intranasal immunization generates antigen-specific T cell and B cell memory throughout the respiratory tract. This includes a population of tissue-resident memory T cells (TRM) that are uniquely positioned within the mucosa to rapidly recognize and respond to re-exposure with a similar pathogen. Often these TRM are specific for highly conserved epitopes that are shared across many viral strains and can therefore provide protection against viral variants. Recently, using a model of natural respiratory virus transmission we demonstrated that CD8+ TRM are sufficient to rapidly identify and eliminate rare, infected cells prior to propagation of the infection. However, the distinct TRM subsets and cell-intrinsic antiviral mechanisms that are important for limiting transmission are unknown, and how these mechanisms impact local epithelial cells to inhibit viral propagation are not well characterized. To address these deficiencies, we propose to use a murine model of Sendai virus transmission to define the cellular interactions and molecular mechanisms that promote TRM- mediated protection against transmission. Finally, we have developed a guinea pig model of influenza virus transmission to investigate the efficacy of T cell-mediated immunity in limiting transmission of a relevant human pathogen. Identifying the characteristics, cellular interactions, and molecular mechanisms of respiratory tract TRM that protect against natural respiratory virus transmission will provide key information for the rational design of future cell-mediated vaccine against respiratory pathogens.