Document text
Principal Investigator: Mitchell H Grayson
Organization: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
Fiscal Year: 2024
Award: $721,121
Funding agency: National Institute of Allergy and Infectious Diseases
Abstract
Respiratory syncytial virus (RSV) infection leads to 2.1 million outpatient visits and 58,000 hospitalizations for
children under 5 years of age. In those 65 years of age or older, RSV accounts for an average of 177,000
hospitalizations and 14,000 deaths annually, with similar mortality rates to influenza. Human data suggest pre-
existing atopy may have a protective effect on mortality and severity of influenza and SARS-CoV-2 infection, and
mouse models have shown protection from influenza mediated mortality with pre-existing atopy; however, the
mechanism of this protection remains unclear. Using the house dust mite model of atopy, we found being atopic
before infection with mouse parainfluenza virus type-1 (Sendai virus; SeV, a murine virus closely related to RSV),
prevented mortality to an otherwise lethal viral dose. This survival depended upon CD11c+ cells, which produced
neureglin-1 (NRG1). NRG1 appears to protect airway epithelium from the viral insult. Two alarmins released in
the house dust mite model, IL33 and TSLP, induced NRG1 production from CD11c+ cells. CD11c+ cells from
atopic mice or exogenous NRG1 reduced viral replication in airway epithelial cells in vitro and NRG1 significantly
reduced mortality in vivo. Based on our data, we propose the hypothesis that pre-existing atopy protects against
respiratory viral induced mortality in an IL33-TSLP dependent process that drives CD11c+ cells to produce
NRG1, which restores epithelial cell homeostasis and protects epithelial cells from viral infection. Using our
mouse model and mouse and human airway epithelial cell cultures to test these hypotheses, we propose to: (I)
Define the NRG1 producing cell(s) in atopic mice and determine the requirement for NRG1 in atopy mediated
survival from normally lethal SeV infection. (II) Determine the effect of NRG1 on epithelial cell function and
protection from a respiratory viral insult. Upon completion of this proposal, we will have identified and
characterized the NRG1 producing cells in the atopic mouse lung, the requirement for these cells and NRG1 in
mediating survival in SeV infected atopic mice, and the requirement for alarmins in the development of the NRG1
producing cells and subsequent survival from the viral infection. In addition, we will have mechanistically
characterized the effect of NRG1 on epithelial cells and determined the potential for NRG1 as a therapeutic
agent. These findings form the basis for future studies to explore therapeutic interventions to prevent mortality
from respiratory viral infections, with great potential to change medical care for severe respiratory viral infections.
Terms: <0-11 years old><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><5 year old><5 years of age><65 and older><65 or older><65 years of age and older><65 years of age or more><65 years of age or older><65+ years><65+ years old><> 65 years><Acetylcholine Receptor Inducing Activity><Adoptive Transfer><Aged 65 and Over><Air><Airway Hyper-responsiveness><Allergic Disease><Antibodies><Asthma><Atopic Allergy><Autoregulation><B-Cell Stimulatory Factor 1 Gene><BSF-1 Gene><BSF1 Gene><Blood Eosinophil><Blood monocyte><Breast Cancer Cell Differentiation Factor P45><Bronchial Asthma><CD11c><CD14><CD14 gene><COVID-19 infection><COVID-19 virus><COVID-19 virus infection><COVID19 infection><COVID19 virus><Caring><Cell Body><Cell Culture Techniques><Cell Function><Cell Physiology><Cell Process><Cell Protection><Cells><Cellular Function><Cellular Infiltrate><Cellular Physiology><Cellular Process><Cessation of life><Child><Child Youth><Children (0-21)><Clinical Treatment Moab><CoV-2><CoV2><Cytoprotection><Data><Death><Death Rate><Dendritic Cells><Development><Disease><Disorder><Dose><Elderly><Eosinophilic Granulocyte><Eosinophilic Leukocyte><Epithelial Cells><Future><Gene Transcription><Genetic Transcription><Goals><Green Fluorescent Proteins><Grippe><HPIV1><Hemadsorption Type 2 Virus><Hemadsorption Virus 2><Hemagglutinating Virus of Japan><Hematopoietic><Homeostasis><Hospital Admission><Hospitalization><Hospitalized Child><House Dust Mites><Housedust Mites><Human><Human Parainfluenza Virus 1><IFN><IL-13><IL-4 Gene><IL13><IL4><IL4 gene><ITGAX><ITGAX gene><Impairment><In Vitro><Infant><Infection><Inflammatory><Influenza><Interferons><Interleukin-13><Interleukin-4 Gene><Interleukin-4 Precursor Gene><Liquid substance><Lung><Lung Respiratory System><Macrophage Activation><Marrow Eosinophil><Marrow monocyte><Mediating><Medical><Metabolic><Metaplasia><Metaplastic Change><Mice><Mice Mammals><Mitochondria><Modeling><Modern Man><Monoclonal Antibodies><Mucous body substance><Mucus><Murine><Mus><NDF Protein><NRG1 Gene Product><NRG1 Protein><Neuregulin 1><Occluding Junctions><Out-patients><Outpatients><Para-Influenza Virus Type 1><Pathway interactions><Physiological Homeostasis><Process><Production><Publications><Pyroglyphidae><RNA Expression><RSV infection><Receptor Protein><Respiratory Epithelium><Respiratory Syncytial Virus Infections><Respiratory syncytial virus><Risk><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 infection><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Scientific Publication><Sendai virus><Sensory And Motor Neuron-Derived Factor><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-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 infection><Severe acute respiratory syndrome related corona virus 2><Severities><Sorting><Stress><Structure of respiratory epithelium><Subcellular Process><TSLP><TSLP gene><Testing><Therapeutic><Therapeutic Agents><Therapeutic Intervention><Therapeutic Studies><Therapy Research><Thymic Stromal Lymphopoietin><Tight Junctions><Transcription><Translating><Veiled Cells><Viral><Viral Diseases><Viral Respiratory Tract Infection><Virus><Virus Diseases><Virus Replication><Visit><Wuhan coronavirus><Zonula Occludens><above age 65><advanced age><after age 65><age 5 years><age 65 and greater><age 65 and older><age 65 or older><age > 65><age of 65 years onward><aged 65 and greater><aged 65+><aged ≥65><airway epithelium><airway hyper-reactivity><airway hyperactivity><airway hyperreactivity><airway hyperresponsiveness><airway hypersensitivity><atopic triad><atopy><cell culture><cell cultures><coronavirus disease 2019 infection><coronavirus disease 2019 virus><coronavirus disease-19 virus><cytoprotective><developmental><eosinophil><experiment><experimental research><experimental study><experiments><five year old><five years of age><fluid><gene product><geriatric><hCoV19><hemopoietic><human data><human old age (65+)><in vivo><infancy><infantile><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><intervention therapy><kids><liquid><mAbs><mitochondrial><monoclonal Abs><monocyte><mortality><mortality rate><mortality ratio><mouse model><mucous><murine model><nCoV2><new approaches><novel approaches><novel strategies><novel strategy><old age><over 65 years><parainfluenza virus><parainfluenza virus type 1><pathogenic virus><pathway><peripheral blood><prevent><preventing><protective effect><pulmonary><receptor><respiratory><respiratory tract epithelium><response><scRNA-seq><senior citizen><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><viral infection><viral multiplication><viral pathogen><viral replication><viral respiratory infection><virus infection><virus multiplication><virus pathogen><virus-induced disease><youngster><≥65 years>