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Principal Investigator: Sofia Caryotakis
Organization: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
Fiscal Year: 2024
Award: $45,909
Funding agency: National Heart Lung and Blood Institute
Project Summary
Respiratory viral infections are a prevalent and ongoing threat to global health, as evidenced by seasonal
Influenza A infections and the SARS-CoV-2 pandemic. Notably, the association between allergy and asthma
and the severity of respiratory viral illness has been long observed but poorly understood. Group 2 innate
lymphoid cells (ILC2s) and the adaptive counterpart Type 2 CD4 helper cells (Th2) have been extensively
investigated for their role in allergic inflammation. Our group has described the localization of these type 2
lymphocytes (T2L) in non-lymphoid tissues, such as the lung, at rest and under allergic and mixed type 1-2
inflammation, observing localization near large airways and vessels at rest and expansion to the tissue
parenchyma with allergic inflammation. Interestingly, in mixed type 1-2 inflammation, T2L parenchymal
distribution is restricted due to Interferon gamma (IFNγ) signaling on T2L. My preliminary data demonstrates that
IFNγ-mediated restriction also occurs following viral respiratory infection with Influenza A virus (IAV, PR8) and
impacts mouse body weight and lung function. In parallel, I have demonstrated that loss IFNα/β signaling on
T2Ls increases body weight loss and impairs lung function in IAV, potentially through a distinct mechanism.
These data suggest that IFN-mediated restriction of T2L and T2L topography is critical for appropriate viral
clearance and/or tissue repair in viral respiratory infection. Mechanisms of IFN-mediated restriction of T2L have
been explored by many groups, including ours, however how this restriction of topography and counter-regulation
of T1 immunity by T2L dictate the immune response to viral infection remains elusive. I hypothesize that IFN
signaling regulates the topography and function of lung T2Ls in pulmonary viral infections. This proposal will
define the topography of T1-T2 cross-regulation in the setting of pulmonary viral infection (Aim 1) and evaluate
mechanism of interferon mediated restriction of type 2 lymphocytes (Aim 2). Completion of these aims will
elucidate the role of canonical type 1 and type 2 cytokines in mediating tissue resident lymphocyte function in
complex inflammation, providing novel mechanistic insight into how topography dictates immunity. Completion
of this study provides a foundation for the development of precision therapeutics to selectively regulate lung
resident lymphocytes subsets to impact the outcome of diverse lung diseases.
Terms: <(IFN) α><(IFN)-α><(IFN)α><3-D Imaging><3-D modeling><3D imaging><3D modeling><Acute><Alferon><Allergic><Allergic Disease><Allergic inflammation><Allergy><Alveolar><Amphiregulin><Apoptotic><Asthma><B Cell Differentiation Factor I><B cell growth factor 2><B-Cell Growth Factor-II><BCGF-II><BCGF2><Bacteria><Body Tissues><Body Weight><Body Weight decreased><Bronchial Asthma><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 infection><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 virus infection><COVID-19 years><COVID19 infection><CRGF><Cell Communication and Signaling><Cell Death><Cell Death Induction><Cell Signaling><Cessation of life><Chronic><Colorectum Cell-Derived Growth Factor><Complex><Confocal Microscopy><Data><Death><Development><Disease><Disorder><Distal><Eo-CSF><Eosinophil Differentiation Factor><Fibroblasts><Foundations><Goals><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Human><Hypersensitivity><IFN><IFN Alpha><IFN α><IFN-Gamma><IFN-g><IFN-α><IFN-γ><IFNG><IFNa><IFNα><IFNγ><IL-13><IL-5><IL13><IgA enhancing factor><Immune><Immune Interferon><Immune response><Immune system><Immunes><Immunity><Immunological response><Impairment><Individual><Inducer Cells><Inducer T-Lymphocytes><Induction of Apoptosis><Infection><Inflammation><Influenza A><Influenza A virus><Influenza Viruses Type A><Influenzavirus A><Interferon Alfa-n3><Interferon Gamma><Interferon Type II><Interferon alpha><Interferon-α><Interferons><Interleukin 5 Precursor><Interleukin-13><Interleukin-5><Intracellular Communication and Signaling><Keratinocyte-Derived Autocrine Factor><L monocytogenes><L. monocytogenes><Leukocyte Interferon><Listeria monocytogenes><Lung><Lung Diseases><Lung Inflammation><Lung Parenchyma><Lung Respiratory System><Lung Tissue><Lung damage><Lung infections><Lymphatic cell><Lymphoblast Interferon><Lymphoblastoid Interferon><Lymphocyte><Lymphocyte Function><Lymphocyte Subpopulations><Lymphocyte Subset><Lymphocytic><Lymphoid Cell><Mediating><Mice><Mice Mammals><Modeling><Modern Man><Morbidity><Morbidity - disease rate><Murine><Mus><Orthomyxovirus Type A><Outcome><Patients><Pneumonitis><Precision therapeutics><Predisposition><Production><Proliferating><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Inflammation><Recovery><Regulation><Repression><Rest><Role><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 infection><SARS-CoV-2 pandemic><SARS-CoV2 infection><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><Schwannoma-Derived Growth Factor><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 pandemic><Severities><Signal Induction><Signal Transduction><Signal Transduction Systems><Signaling><Source><Structure of parenchyma of lung><Susceptibility><T cell replacing factor><T-Cell Replacing Factor><Testing><Three-Dimensional Imaging><Tissues><Type A Influenza><Viral><Viral Diseases><Viral Respiratory Tract Infection><Virus Diseases><Weight Gain><Weight Increase><Weight Loss><Weight Reduction><Work><apoptosis in lymphocytes><apoptotic lymphocytes><arm><asthma attack><asthma exacerbation><biological signal transduction><body weight gain><body weight increase><body weight loss><colorectal cell-derived growth factor><colorectal-associated growth factor><colorectum-associated growth factor><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 infection><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><counterregulation><cytokine><design><designing><developmental><disease of the lung><disorder of the lung><exacerbation in asthma><exacerbation prone asthma><exacerbation prone asthmatic><global health><host response><immune system response><immunoresponse><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><insight><keratinocyte autocrine factor><lFN-Gamma><lung disorder><lung function><lung injury><lymph cell><lymphocyte apoptosis><lymphocyte effector molecules><lymphocyte trafficking><mortality><necrocytosis><novel><pathogen><precision therapies><precision treatment><pulmonary><pulmonary damage><pulmonary function><pulmonary infections><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><respiratory><response><seasonal flu><seasonal influenza><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><social role><three-dimensional modeling><tissue repair><trafficking><transcriptomics><viral infection><viral respiratory infection><virus infection><virus-induced disease><wt gain><wt-loss>