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Principal Investigator: JACOB E KOHLMEIER
Organization: EMORY UNIVERSITY
Fiscal Year: 2024
Award: $640,735
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY / ABSTRACT
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. While previous studies have shown that TRM can
mediate protection by limiting viral replication and immunopathology following direct inoculation, it is not known
whether TRM alone can effectively surveil the large surface area of the respiratory epithelium to rapidly identify
and eliminate rare, infected cells during natural transmission events prior to propagation of the infection
throughout the respiratory tract. Furthermore, the TRM antiviral mechanisms that are important for limiting
transmission are unknown, and how these mechanisms impact local innate and epithelial cells inhibit viral
propagation are not well characterized. To address these deficiencies, we have developed a murine model of
Sendai virus transmission, and new experimental tools to establish Sendai virus-specific respiratory tract TRM
without generating Sendai-specific antibody. Our preliminary data show that Sendai-specific respiratory tract
CD8+ TRM protected mice from propagation of infection following transmission events, whereas mice with only
circulating Sendai-specific CD8+ memory T cells were not protected. Finally, in collaboration with Dr. Anice
Lowen (co-I), we have developed a guinea pig model of heterosubtypic influenza virus transmission to
investigate the efficacy of T cell-mediated immunity in limiting transmission of a relevant human pathogen. This
proposal will investigate the characteristics, durability, and molecular mechanisms of respiratory tract TRM that
protect against natural respiratory transmission.
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epithelium><Surface><T cell response><T memory cell><T-Cell Epitopes><T-Cells><T-Lymphocyte><T-Lymphocyte Epitopes><T8 Cells><T8 Lymphocytes><Testing><Tissue Distribution><Transmission><Up-Regulation><Upper respiratory tract><Upregulation><Vaccinated><Vaccination><Vaccination Programs><Vaccine Design><Vaccines><Variant><Variation><Viral><Virus><Virus Replication><Wuhan coronavirus><adeno vector><adenovector><airway epithelium><anti-viral immunity><antigen-specific T cells><antiviral immunity><burden of disease><burden of illness><conditional knock-out><conditional knockout><coronavirus disease 2019 variant><coronavirus disease 2019 variant forms><coronavirus disease 2019 variant strains><coronavirus disease 2019 virus><coronavirus disease-19 virus><cytokine><cytoprotective><determine efficacy><developmental><disease burden><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><evaluate efficacy><examine efficacy><flu><flu HA><flu 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