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Principal Investigator: Montserrat C Anguera
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2022
Award: $241,688
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
COVID-19, the disease caused by the SARS-CoV-2 virus, commonly presents as pneumonia, with those most
severely affected progressing to Acute Respiratory Distress Syndrome (ARDS). Notably, males seem to be at
significantly higher risk for severe or fatal outcomes from COVID-19, and male-specific skewing was also
observed with related coronaviruses SARS-CoV and MERS. The X chromosome is enriched for immunity-related
genes, and females (XX) mount stronger immune responses than do males (XY). X-chromosome Inactivation
(XCI) normalizes the gene dosage effect between the sexes and we have previously found that immune cells
have novel and dynamic XCI mechanisms that allow for gene-specific transcriptional activation from the inactive
X (Xi) in a cell-type specific manner. Notably, our preliminary data suggest the regulation of XCI in lung alveolar
type 2 (AT2) cells, the predominant target of SARS-CoV-2 in the lung and a cell type critically involved in lung
repair following viral injury, phenocopies that seen in immune cells. As such, we will test the novel hypothesis
that X-linked genes, including immune genes and ACE2, escape XCI in a lineage-specific fashion and contribute
to the relative resistance of females to COVID-19 (Aim 1). We will test the hypothesis that our novel humanized
ACE2 mice, which are susceptible to SARS-CoV-2 infection, will exhibit sex differences with resulting lung
pathologies in aged mice (Aim 2). Together, these studies will further our understanding of the mechanisms that
predispose males to COVID-19 disease and will reveal novel strategies to reduce disease severity.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ACE2><ARDS><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Affect><Age><Alveolar><AngII><Angiotensin AT2 Receptor><Angiotensin II><Angiotensin Receptor 2><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><COVID><COVID associated morbidity><COVID disease severity><COVID induced morbidity><COVID morbidity><COVID related morbidity><COVID severity><COVID-19><COVID-19 associated death><COVID-19 associated fatality><COVID-19 associated morbidity><COVID-19 associated mortality><COVID-19 death><COVID-19 disease severity><COVID-19 fatality><COVID-19 induced death><COVID-19 induced fatality><COVID-19 induced morbidity><COVID-19 induced mortality><COVID-19 infection><COVID-19 morbidity><COVID-19 mortality><COVID-19 predisposition><COVID-19 related death><COVID-19 related fatality><COVID-19 related morbidity><COVID-19 related mortality><COVID-19 severity><COVID-19 susceptibility><COVID-19 therapy><COVID-19 treatment><COVID-19 virus><COVID-19 vulnerability><COVID19><COVID19 associated death><COVID19 associated fatality><COVID19 associated mortality><COVID19 death><COVID19 disease severity><COVID19 fatality><COVID19 induced death><COVID19 induced fatality><COVID19 induced mortality><COVID19 infection><COVID19 mortality><COVID19 related death><COVID19 related fatality><COVID19 related mortality><COVID19 severity><COVID19 therapy><COVID19 treatment><COVID19 virus><CV-19><CV19><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><CoV disease><CoV emergence><CoV-2><CoV2><Code><Coding System><Coronaviridae><Coronavirus><Coronavirus disease 2019 predisposition><Coronavirus disease 2019 susceptibility><Coronavirus disease 2019 vulnerability><Da Nang Lung><Data><Development><Differences between sexes><Differs between sexes><Disease><Disease Outbreaks><Disease Outcome><Disease Progression><Disease model><Disorder><Elements><Endocrine Gland Secretion><Endothelial Cells><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Estrogen Therapy><Estrogens><Exhibits><Fatal Outcome><Female><Future><Gender Bias><Gene Copy Number><Gene Dosage><Genes><Genetic><Gonadal Steroid Hormones><Hormonal><Hormone Responsive><Hormones><Host Factor><Host Factor Protein><Human><Hybrids><Immune><Immune response><Immunes><Immunity><Immunological response><Infection><Inflammatory><Inflammatory Response><Injury><Integration Host Factors><Intracellular Communication and Signaling><Link><Lung><Lung Respiratory System><Lyonization><MERS><MERS coronavirus disease><MERS-CoV disease><Mice><Mice Mammals><Middle East Respiratory Syndrome><Middle East Respiratory Syndrome CoV disease><Middle East Respiratory Syndrome coronavirus disease><Middle Eastern Respiratory Syndrome><Middle Eastern Respiratory Syndrome CoV disease><Middle Eastern Respiratory Syndrome coronavirus disease><Modern Man><Morbidity><Morbidity - disease rate><Murine><Mus><Mφ><Outbreaks><Outcome><Pathology><Pathway interactions><Pattern><Peripheral><Phenocopy><Pneumonia><Population><Predisposed to COVID-19><Predisposed to SARS-CoV-2><Predisposed to Severe acute respiratory syndrome coronavirus 2><Predisposition><Pulmonary Pathology><RNA Seq><RNA sequencing><RNAseq><Receptor Protein><Receptor, Angiotensin, Type 2><Regulation><Regulatory Element><Resistance><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS-Associated Coronavirus><SARS-CO-V2><SARS-COVID-2><SARS-CoV><SARS-CoV-1><SARS-CoV-2><SARS-CoV-2 associated death><SARS-CoV-2 associated fatality><SARS-CoV-2 associated mortality><SARS-CoV-2 death><SARS-CoV-2 disease severity><SARS-CoV-2 fatality><SARS-CoV-2 induced death><SARS-CoV-2 induced fatality><SARS-CoV-2 induced mortality><SARS-CoV-2 infection><SARS-CoV-2 mortality><SARS-CoV-2 predisposition><SARS-CoV-2 related death><SARS-CoV-2 related fatality><SARS-CoV-2 related mortality><SARS-CoV-2 severity><SARS-CoV-2 susceptibility><SARS-CoV-2 therapy><SARS-CoV-2 treatment><SARS-CoV-2 vulnerability><SARS-CoV2><SARS-CoV2 infection><SARS-Related Coronavirus><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Severe Acute Respiratory Coronavirus><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 Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><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 corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 predisposition><Severe acute respiratory syndrome coronavirus 2 susceptibility><Severe acute respiratory syndrome coronavirus 2 vulnerability><Severe acute respiratory syndrome related corona virus 2><Severity of illness><Sex Bias><Sex Differences><Sex Hormones><Sex Steroid Hormones><Sexual differences><Shock Lung><Signal Transduction><Signal Transduction Systems><Signaling><Stiff lung><Supplementation><Susceptibility><System><T4 Cells><T4 Lymphocytes><Testing><Therapeutic Estrogen><Therapeutic Hormone><Transcript><Transcription Activation><Transcriptional Activation><Transgenic Mice><Type 2 Angiotensin II Receptor><Vascular Diseases><Vascular Disorder><Viral><Viral Diseases><Virus><Virus Diseases><Wild Type Mouse><Woman><Wuhan coronavirus><X Chromosome><X Inactivation><X-Chromosome Inactivation><after COVID-19 infection><after SARS-CoV-2 infection><after SARS-CoV2 infection><after severe acute respiratory distress syndrome CoV-2 infection><age dependent><age related><aged><ages><angiotensin converting enzyme 2><angiotensin converting enzyme II><biological signal transduction><blood vessel disorder><burden of disease><burden of illness><cell type><corona virus><corona virus disease><corona virus disease 2019><corona virus emergence><coronavirus disease><coronavirus disease 2019><coronavirus disease 2019 associated death><coronavirus disease 2019 associated fatality><coronavirus disease 2019 associated morbidity><coronavirus disease 2019 associated mortality><coronavirus disease 2019 death><coronavirus disease 2019 disease severity><coronavirus disease 2019 fatality><coronavirus disease 2019 induced death><coronavirus disease 2019 induced fatality><coronavirus disease 2019 induced morbidity><coronavirus disease 2019 induced mortality><coronavirus disease 2019 infection><coronavirus disease 2019 morbidity><coronavirus disease 2019 mortality><coronavirus disease 2019 related death><coronavirus disease 2019 related fatality><coronavirus disease 2019 related morbidity><coronavirus disease 2019 related mortality><coronavirus disease 2019 severity><coronavirus disease 2019 therapy><coronavirus disease 2019 treatment><coronavirus disease 2019 virus><coronavirus disease associated morbidity><coronavirus disease induced morbidity><coronavirus disease morbidity><coronavirus disease related morbidity><coronavirus disease severity><coronavirus disease-19><coronavirus disease-19 mortality><coronavirus disease-19 virus><coronavirus emergence><coronavirus infectious disease-19><cytokine><death due to COVID-19><death due to COVID19><death due to SARS-CoV-2><death due to coronavirus disease 2019><death due to severe acute respiratory syndrome coronavirus 2><death in COVID><death in COVID-19><death in SARS-CoV-2><death in coronavirus disease><death in coronavirus disease 2019><death in severe acute respiratory syndrome coronavirus 2><developmental><disease burden><disease severity><disorder model><emergent CoV><emergent corona virus><emergent coronavirus><emerging CoV><emerging corona virus><emerging coronavirus><estrogen treatment><fatality due to COVID-19><fatality due to COVID19><fatality due to SARS-CoV-2><fatality due to coronavirus disease 2019><fatality due to severe acute respiratory syndrome coronavirus 2><following COVID-19 infection><following SARS-CoV-2 infection><following SARS-CoV2 infection><following severe acute respiratory distress syndrome CoV-2 infection><gonadal steroids><hCoV19><high risk><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><injuries><insight><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><lung pathology><lung repair><lung tissue repair><macrophage><male><men><men's><mortality><mortality due to COVID-19><mortality due to COVID19><mortality due to SARS-CoV-2><mortality due to coronavirus disease 2019><mortality due to severe acute respiratory syndrome coronavirus 2><mouse model><murine model><nCoV><nCoV2><new CoV><new approaches><new corona virus><new coronavirus><novel><novel CoV><novel approaches><novel corona virus><novel coronavirus><novel strategies><novel strategy><pathway><post SARS-CoV-2 infection><predisposed to Coronavirus disease 2019><preservation><prevent><preventing><previous COVID-19 infection><previous SARS-CoV-2 infection><previous SARS-CoV2 infection><previous severe acute respiratory distress syndrome CoV-2 infection><prior COVID-19 infection><prior SARS-CoV-2 infection><prior SARS-CoV2 infection><prior severe acute respiratory distress syndrome CoV-2 infection><promoter><promotor><pulmonary><pulmonary repair><receptor><resistant><respiratory><response><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe acute respiratory syndrome coronavirus 2 associated death><severe acute respiratory syndrome coronavirus 2 associated fatality><severe acute respiratory syndrome coronavirus 2 associated mortality><severe acute respiratory syndrome coronavirus 2 death><severe acute respiratory syndrome coronavirus 2 disease severity><severe acute respiratory syndrome coronavirus 2 fatality><severe acute respiratory syndrome coronavirus 2 induced death><severe acute respiratory syndrome coronavirus 2 induced fatality><severe acute respiratory syndrome coronavirus 2 induced mortality><severe acute respiratory syndrome coronavirus 2 mortality><severe acute respiratory syndrome coronavirus 2 related death><severe acute respiratory syndrome coronavirus 2 related fatality><severe acute respiratory syndrome coronavirus 2 related mortality><severe acute respiratory syndrome coronavirus 2 severity><severe acute respiratory syndrome coronavirus 2 therapy><severe acute respiratory syndrome coronavirus 2 treatment><severe acute respiratory syndrome-CoV><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><sex><sex steroid><sex-dependent differences><sex-related differences><sex-specific differences><susceptible to COVID-19><susceptible to Coronavirus disease 2019><susceptible to SARS-CoV-2><susceptible to Severe acute respiratory syndrome coronavirus 2><transcriptome sequencing><treat COVID-19><treat COVID19><treat SARS-CoV-2><treat coronavirus disease 2019><treat severe acute respiratory syndrome coronavirus 2><treated with estrogen><treatment with estrogen><vascular dysfunction><vasculopathy><viral infection><virus infection><virus-induced disease><wet lung><wildtype mouse><years of life lost to disability><years of life lost to disease>