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Principal Investigator: Xingbin Ai
Organization: MASSACHUSETTS GENERAL HOSPITAL
Fiscal Year: 2024
Award: $208,750
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
COVID-19 (CoV19) is caused by SARS-CoV-2 infection of the airway epithelium resulting in extensive
damage in the lower respiratory tract. Since 2020, CoV19 has claimed over 1 million lives in the United
States surpassing the death toll of the 1918 H1N1 influenza pandemic. Clinical studies show that the
mortality and morbidity of CoV19 is associated with secondary infection. Given a central role of the airway
epithelium as a barrier against pathogens, preliminary studies tested whether airway basal stem cells
(BSCs) are impaired in their regenerative function in CoV19 patients. Of note, BSCs are a major type of
stem cells responsible for epithelium regeneration following respiratory viral infection in humans. In
preliminary studies, we derived 6 lines of BSCs from severe cases of CoV19 using tracheal aspirate (TA)
as a source of bronchial BSCs. These CoV19-exposed BSCs were tested free of virus; however, they
show early cell cycle arrest, sustained STAT3 hyperactivity, and defective differentiation in air-liquid
interface. In contract, BSCs derived from TA of control patients with neurogenic and cardiogenic
respiratory failure have no such defects. Similar to our findings in vitro, antibody staining of fatal CoV19
lung sections revealed increased senescence and defective differentiation of BSCs. In addition, CoV19-
exposed BSCs in vitro maintained, at least partially, an inflammatory gene signature that was found in
BSCs in vivo by single cell-seq of lung samples from CoV19 patients. As such, BSCs derived from TA of
CoV19 patients provide a viable cell model to investigate how CoV19 impairs epithelial regeneration by
inducing an inflammatory memory in BSCs. Mechanistically, CoV19-exposed BSCs exhibit unique
chromatin opening at sites enriched for transcriptional factors mediating the inflammatory pathways, such
as STAT3. Based on these preliminary findings, we hypothesize that inflammation in CoV19 causes
an epigenetic memory in BSCs to impair epithelium regeneration. Leveraging our ability to derive
TA BSCs, Aim1 will test whether CoV19 uniquely reprograms BSCs compared to other acute respiratory
infections. Aim 2 will identify the molecular mediators of the inflammatory memory in CoV19-exposed
BSCs using complementary assays. The rescue assay will test whether blocking STAT3 hyperactivity
and reversing epigenetic modification in CoV19-exposed BSCs will normalize their role in epithelial
regeneration. The disease-mimicking assay will assess the activity of inflammatory signals in memory
induction in healthy control BSCs. The proposed exploratory studies will lay the foundation for future
delineation of inflammatory signals and intracellular mediators in the disease memory of BSCs using
genetic approaches and animal models of SARS-CoV-2 infection. Our findings will inform therapeutics to
facilitate epithelial regeneration in severe cases of CoV19.
Terms: <1918 H1N1><1918 influenza A virus><1918 influenza H1N1 virus><1918 influenza virus><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ATAC sequencing><ATAC-seq><ATACseq><Acute respiratory infection><Age><Air><Airway failure><Airway infections><Animal Model><Animal Models and Related Studies><Antibodies><Assay><Assay for Transposase-Accessible Chromatin using sequencing><Basal Cell><Basal Transcription Factor><Basal transcription factor genes><Bioassay><Biological Assay><Biopsy><COVID-19><COVID-19 affected><COVID-19 consequence><COVID-19 effect><COVID-19 impact><COVID-19 impacted><COVID-19 infection><COVID-19 negative><COVID-19 virus><COVID-19 virus infection><COVID19 infection><COVID19 negative><COVID19 virus><CV-19><Cell Body><Cell Communication and Signaling><Cell Cycle Arrest><Cell Isolation><Cell Line><Cell Segregation><Cell Separation><Cell Separation Technology><Cell Signaling><Cell Survival><Cell Viability><Cell model><CellLine><Cells><Cellular model><Cessation of life><Chemotactic Cytokines><Chromatin><Chronic lung disease><Clinical Research><Clinical Study><CoV-2><CoV2><Contracting Opportunities><Contracts><Coronaviridae><Coronavirus><Coronavirus Infectious Disease 2019><Death><Defect><Derivation><Derivation procedure><Disease><Disorder><Dysfunction><ENX-1><EZH1><EZH2><EZH2 gene><Endowment><Enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epithelium><Exhibits><Foundations><Functional disorder><Future><Gene Expression><General Transcription Factor Gene><General Transcription Factors><Genetic study><Goals><Health><Homologous Chemotactic Cytokines><Human><Hyperactivity><Immune><Immunes><Impairment><In Vitro><Infection><Inflammation><Inflammation Mediators><Inflammatory><Innate Immunity><Intercrines><Intracellular Communication and Signaling><Intubation><KMT6><KMT6A><Lead><Liquid substance><Lower respiratory tract structure><Lung><Lung Diseases><Lung Respiratory System><Mediating><Mediator><Medical Waste><Memory><Methods><Mice><Mice Mammals><Microscopic><Modeling><Modern Man><Modification><Molecular><Morbidity><Morbidity - disease rate><Murine><Mus><Native Immunity><Natural Immunity><Non-Specific Immunity><Nonspecific Immunity><Olfactory Pathways><Olfactory system><Organ><Pathogenesis><Pathway interactions><Patient Care><Patient Care Delivery><Patients><Pb element><Phenotype><Physiopathology><Play><Procedures><Progenitor Cells><Proliferating><Pulmonary Diseases><Pulmonary Disorder><Receptor Protein><Research><Respiratory Disease><Respiratory Epithelium><Respiratory Failure><Respiratory Infections><Respiratory System Disease><Respiratory System Disorder><Respiratory Tract Infections><Risk><Risk Reduction><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 infection><SARS-CoV-2 negative><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><SIS cytokines><STAT3><STAT3 gene><Sampling><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><Signal Transduction><Signal Transduction Systems><Signaling><Single cell seq><Site><Skin><Source><Spanish flu><Spanish influenza><Staining method><Stains><Stem Cell like><Strains Cell Lines><Structure of respiratory epithelium><Testing><Therapeutic><Trachea><Trachea Proper><Transcription Factor Proto-Oncogene><Transcription factor genes><Type II Pneumocyte><United States><Viral Respiratory Tract Infection><Virus><Wuhan coronavirus><acute infection><ages><airway epithelium><alveolar type II cell><aspirate><assay for transposase accessible chromatin followed by sequencing><assay for transposase accessible chromatin seq><assay for transposase accessible chromatin sequencing><assay for transposase-accessible chromatin with sequencing><biological signal transduction><care for patients><care of patients><caring for patients><cell sorting><chemoattractant cytokine><chemokine><chronic pulmonary disease><corona virus><coronavirus disease 2019><coronavirus disease 2019 consequence><coronavirus disease 2019 effect><coronavirus disease 2019 impact><coronavirus disease 2019 infection><coronavirus disease 2019 negative><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 impact><coronavirus disease-19 virus><coronavirus infectious disease-19><cultured cell line><cytokine><disease of the lung><disorder of the lung><epigenetic memory><epigenetically><epithelial progenitor><epithelial progenitor cell><epithelial stem cell><epithelium regeneration><flu virus pandemic><fluid><gene locus><gene signatures><genetic approach><genetic locus><genetic signature><genetic strategy><genomic location><genomic locus><global gene expression><global transcription profile><hCoV19><heavy metal Pb><heavy metal lead><imprint><in vivo><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><inflammatory mediator><influenza virus pandemic><liquid><lower respiratory tract><lung disorder><model of animal><mortality><multi-modality><multimodality><nCoV2><olfactory circuitry><olfactory circuits><pandemic><pandemic disease><pandemic flu><pandemic influenza><pandemic strain of influenza><pathogen><pathophysiology><pathway><prevent><preventing><progenitor cell proliferation><progenitor proliferation><programs><pulmonary><receptor><reduce risk><reduce risks><reduce that risk><reduce the risk><reduce these risks><reduces risk><reduces the risk><reducing risk><reducing the risk><regenerate epithelium><regeneration function><regenerative function><regenerative functionality><respiratory><respiratory tract epithelium><response><risk-reducing><secondary infection><senescence><senescent><severe acute respiratory syndrome coronavirus 2 negative><single cell next generation sequencing><single cell sequencing><social role><stem and progenitor cell proliferation><stem cell characteristics><stem cell proliferation><stem cells><stemness><therapeutic target><transcription factor><transcriptome><viral respiratory infection><windpipe>