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Principal Investigator: Marulasiddappa Suresh
Organization: UNIVERSITY OF WISCONSIN-MADISON
Fiscal Year: 2024
Award: $194,375
Funding agency: National Institute of Allergy and Infectious Diseases
Abstract: Respiratory infections have been among the top three leading causes of global deaths for decades. Their
importance is reinforced by the emergence of novel highly transmissible respiratory pathogens, as witnessed in the current
SARS-CoV-2 and past influenza pandemics. Current influenza and SARS-CoV-2 vaccines are focused on eliciting
antibodies to highly mutable viral surface proteins, and frequent vaccine reformulations are needed to match the antigenicity
of constantly evolving viral strains or variants that evade vaccine-elicited antibodies. Therefore, elicitation of lung tissue-
resident memory T cells (TRMs), which recognize epitopes that are conserved across viral variants is critical to elicit broad
anti-viral immunity. We have developed combination adjuvant-based subunit mucosal vaccine formulations that elicit
exceptionally strong and functionally diverse lung/airway CD8 and CD4 TRMs and provide effective and broad
protection against influenza A virus (IAV) and SARS-CoV-2 in specific-pathogen-free (SPF) mice. However, a central
question is whether vaccine efficacy studies in SPF mice are translatable to humans, who are exposed to diverse
microbial species. In recent years, Dirty mice (SPF mice cohoused with pet store mice), have been used to model human
immune responses. Significantly, TRM numbers are greatly increased in Dirty mice, but the underlying mechanisms are
unknown. We have exciting preliminary data that the lungs and spleen of Dirty mice have markedly elevated number of
Granzyme BHI/CD44HI CD8 T cells with transcriptional attributes (T-betLO/EOMESLO/TCF-1LO) reminiscent of precursor
TRMs, which are poised for a TRM cell fate. The overarching goal is to exploit the high resolution of our combination
adjuvant-based vaccine approach and the Dirty mouse model to elucidate the effects of diverse microbial exposure on the
development of pre-TRMs and their subsequent differentiation into TRMs that protect against respiratory viruses. Specific
Aim 1 will test the hypothesis that diverse microbial exposure influences the development and protective functions of lung
TRMs against IAV and SARS-CoV-2. Here, we will compare the development and transcriptional programming of lung TRMs
induced by two combination adjuvant vaccine formulations and protective immunity to IAV and SARS-CoV-2 in SPF and
Dirty mice. Specific Aim 2 will test the hypothesis that diverse microbial exposure promotes the conditioning of
circulating/lymphoid pre-TRMs, leading to enhanced differentiation of TRMs in lungs of vaccinated Dirty mice. Here, in Dirty
and SPF mice, we will incisively dissect whether diverse microbial exposure enhances the pre-conditioning of naïve CD8
or CD4 T cells prior to vaccination and/or antigen-activated effector T cells during vaccination, to a TRM cell fate.
Impact:. Proposed studies will leverage microbial exposure to improve the rigor of mouse models to predict human
immune response to vaccines, and provide mechanistic insights into the development of TRMs in the lung under conditions
of diverse microbial exposure. Hence, this exploratory ‘high pay off’ R21 application blends significance and innovation
to lay the conceptual framework for further mechanistic investigations that will pave the way for the development of a
biologically relevant and translatable pre-clinical animal model to learn how we can leverage microbiota to enhance vaccine-
induced T-cell immunity to IAV and SARS-CoV-2, which are human respiratory viruses of public health importance.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV vaccine><Acylneuraminyl hydrolase><Adjuvant><Agonist><Airway infections><Animal Model><Animal Models and Related Studies><Antibodies><Antigenic Determinants><Antigens><Binding Determinants><Biomedical Research><Body Tissues><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><COVID-19 vaccine><COVID-19 virus><COVID19 virus><Cell Body><Cell Count><Cell Number><Cell Protection><Cells><Cessation of life><CoV-2><CoV2><Communicable Diseases><Cytoprotection><Data><Death><Development><Epithelium><Epitopes><Exposure to><Formulation><Gene Transcription><Generalized Growth><Genetic><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Goals><Granzyme><Grippe><Growth><Hemagglutinin><Homolog of Drosophila TOLL><Human><Immune response><Immunity><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Inbred Mouse><Inbreeding><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Influenza><Influenza A><Influenza A virus><Influenza Vaccines><Influenza Virus><Influenza Viruses Type A><Influenzavirus A><Intranasal Administration><Intranasal Drug Administration><Investigation><LYT3><Learning><Link><Lipid A><Lung><Lung Parenchyma><Lung Respiratory System><Lung Tissue><Lymphoid><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Memory><Mice><Mice Mammals><Microbe><Modern Man><Molecular><Mucosa><Mucosal Tissue><Mucous Membrane><Murine><Mus><Mutation><N-Acylneuraminate Glycohydrolases><Neuraminidase><Nucleoproteins><Oligosaccharide Sialidase><Orthomyxovirus Type A><Proteins><Public Health><Pulmonary Body System><Pulmonary Organ System><RNA Expression><Research><Resolution><Respiratory Infections><Respiratory System><Respiratory Tract Infections><Respiratory Tracts><Respiratory tract structure><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 vaccine><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 vaccine><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Seasons><Seminal><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 vaccine><Severe acute respiratory syndrome related corona virus 2><Sialidase><Site><Spleen><Spleen Reticuloendothelial System><Structure of parenchyma of lung><Subunit Vaccines><Surface><Surface Proteins><T cell response><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><TLR4><TLR4 gene><Teff cell><Testing><Time><Tissue Differentiation><Tissue Growth><Tissues><Toll Homologue><Transcription><Translating><Type A Influenza><Vaccinated><Vaccination><Vaccine Research><Vaccines><Variant><Variation><Viral><Viral Diseases><Viral Respiratory Tract Infection><Virus Diseases><Work><Wuhan coronavirus><anti-viral immunity><antiviral immunity><clinical practice><community microbes><conditioning><coronavirus disease 2019 vaccine><coronavirus disease 2019 virus><coronavirus disease-19 vaccine><coronavirus disease-19 virus><cytoprotective><develop a vaccine><develop vaccines><development of a vaccine><developmental><effector T 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