Impact of Resident Memory CD8 T Cells on Respiratory Virus Transmission

项目总结/文摘

PROJECT SUMMARY/ABSTRACT Intranasal vaccination and respiratory virus infection induces populations of antigen specific B cells and T cells in mucosal tissues. The resulting memory T cells recognize internal epitopes that are conserved across viral strains and can provide protection against antigenically novel, potentially pandemic variants. One subset of memory T cells includes tissue resident memory T cells (TRM) which are poised to provide rapid immune responses at the site of pathogen entry. Numerous studies using direct intranasal inoculation have demonstrated that CD8 TRM in the respiratory tract can mediate protection against heterosubtypic influenza strains. However, the ability of CD8 TRM to limit natural respiratory virus transmission has not been defined. Because murine adapted influenza viruses do not readily transmit between mice and immunological reagents for ferret and guinea pig models are limited, studying the immunological mechanisms behind transmission has been significantly hindered. To bridge this gap in knowledge, we developed a murine model using Sendai virus, a mouse parainfluenza virus which naturally transmits between mice. Through the use of a Luciferase encoding Sendai virus, transmission dynamics can be evaluated by in vivo imaging. Our preliminary data demonstrates that Sendai virus specific CD8 TRM in the respiratory tract limit transmission of Sendai virus to immunized contacts. We seek to further define the mechanisms underlying this TRM mediated protection against transmission by evaluating relative contributions of TRM in different anatomical compartments of the respiratory tract. Because studies have demonstrated that a decline in lung and airway TRM corresponds to a loss of heterosubtypic immunity, we will evaluate the durability of TRM mediated protection following various vaccination strategies. Furthermore, we will investigate the TRM antiviral mechanisms that limit transmission with a focus on cytokines and cytolytic proteins. Understanding cellular immune mechanisms in respiratory virus transmission will impact future vaccine development designed to prevent respiratory virus outbreaks.