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Principal Investigator: Hua Linda Cai
Organization: UNIVERSITY OF CALIFORNIA LOS ANGELES
Fiscal Year: 2022
Award: $155,866
Funding agency: National Heart Lung and Blood Institute
ABSTRACT
The central focus of this Administrative Supplement application to is to identify detailed molecular mechanisms of
estrogen-dependent sex difference in COVID-19 to enable development of novel therapeutics that are in urgent need
to control the pandemic. The outbreak of coronavirus disease 2019 (COVID-19) has become a worldwide pandemic
that has remained uncontained. We have previously published a classical article to recognize sex difference of
COVID-19 for the first time, documenting that males are more susceptible to COVID-19 than females, and more often
to develop more severe disease with higher mortality (Cai H, Lancet Respiratory Medicine, April 2020, Citation: 549
by 01/22/22). This important observation has been further confirmed by additional literatures. The gender difference
observed in COVID-19 patients is potentially linked to higher prevalence of cigarette smoking in men that was shown
to be associated with higher viral receptor ACE2 levels. However, we found that protein levels of ACE2 and TMPRSS2
were not changed in endothelial cells exposed to cigarette smoking extract (CSE). The otherwise observed worse
outcomes in COVID-19 patients who are smokers, is likely linked to baseline respiratory diseases associated with
chronic smoking. Instead, we hypothesize that estrogen mediated protection might however underlie less severe
disease in females, and that short term estrogen administration might be used as a robust therapeutic option for the
treatment of COVID-19, especially in men and postmenopausal women. This is supported by strong preliminary data
and our latest publication indicating that SARS-CoV-2 spike protein (S protein) and interleukin-6 (IL-6) stimulated
endothelial cell NADPH oxidase isoform 2 (NOX2) activation and oxidative stress, as well as upregulation of viral
receptor ACE2 and inflammatory protein MCP-1, were all substantially attenuated by estrogen treatment (Redox
Biology, Aug 2021). The upregulation in NOX2 and MCP-1 by S protein is mediated by activation of ACE2 since
blockage of ACE2 with neutralizing antibody was able to abrogate the responses. These data indicate that oxidative
stress and endothelial dysfunction triggered by initial viral infection (S protein), and by cytokine storm (IL-6) at later
stage, which represent major pathological features of acute lung injury (ALI)/acute respiratory distress syndrome
(ARDS)/multi-organ failure, can all be remarkably alleviated by estrogen to effectively reduce disease severity and
mortality. The current project aims to address two specific aims: 1) To examine whether estrogen treatment alleviates
SARS-CoV-2 S protein induced ALI/ARDS and multi-organ injuries in vivo via abrogation of p22phox and p47phox-
dependent activation of NOX2 and activation of netrin-1 signaling. 2) To identify and validate novel genes and gene
pathways/networks regulated by S protein and estrogen with a special focus on netrin-1 signaling, enabling
discoveries of novel therapeutic targets. Overall, accomplishments of both of highly mechanistic and well-integrated
aims will no doubt reveal novel sex difference related molecular mechanisms of COVID-19, targeting of which would
facilitate development of innovative therapies urgently in need to control the devastating pandemic.
Terms: <2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><ACE2><ARDS><Acute Lung Injury><Acute Pulmonary Injury><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Address><Administrative Supplement><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Assay><Attenuated><Autopsy><Azovan Blue><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Bioassay><Biologic Assays><Biological Assay><Biology><CCL2><CCL2 gene><COVID infected patient><COVID patient><COVID positive patient><COVID-19 S protein><COVID-19 infected patient><COVID-19 outbreak><COVID-19 patient><COVID-19 positive patient><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID19 S protein><COVID19 outbreak><COVID19 patient><COVID19 positive patient><COVID19 spike glycoprotein><COVID19 spike protein><CaM KII><CaM PK II><CaM kinase II><CaMKII><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell membrane><Cells><Cellular injury><Cessation of life><Chemokine, CC Motif, Ligand 2><Chronic><Cytoplasmic Membrane><Da Nang Lung><Data><Death><Development><Diagnostic><Differences between sexes><Differs between sexes><Disease><Disease Outbreaks><Disorder><Dysfunction><ERK 1><ERK1><ERK1 Kinase><Endothelial Cells><Endothelium><Epithelial><Epitheliasin Gene><Estrogen Therapy><Estrogens><Evans Blue><Evans blue stain><Exposure to><Extracellular Signal-Regulated Kinase 1><FLJ12216><Female><Functional disorder><Genes><HPGF><Heart><Hepatocyte-Stimulating Factor><High Prevalence><Hybridoma Growth Factor><IFN-beta 2><IFNB2><IL-6><IL6 Protein><Infection><Inflammation><Inflammatory><Injury><Innovative Therapy><Interleukin-6><Intracellular Communication and Signaling><Isoforms><K-18><K-18 conjugate><K18><K18 combination><Kidney><Kidney Urinary System><Link><Literature><Lung><Lung Parenchyma><Lung Respiratory System><Lung Tissue><Lung damage><MAP Kinase 3><MAPK3><MAPK3 Mitogen-Activated Protein Kinase><MAPK3 gene><MCAF><MCP-1><MCP1><MGI-2><MLCK><MLCK108><MLCK210><MOF syndrome><MYLK><MYLK gene><Mediating><Medicine><Methodology><Mice><Mice Mammals><Mitogen-Activated Protein Kinase 3><Mitogen-Activated Protein Kinase 3 Gene><Molecular><Monocyte Chemoattractant Protein-1><Monocyte Chemotactic Protein-1><Monocyte Chemotactic and Activating Factor><Monocyte Chemotactic and Activating Protein><Monocyte Chemotactive and Activating Factor><Monocyte Secretory Protein JE><Mouse Homolog of NETRIN 1><Multiple Organ Dysfunction Syndrome><Multiple Organ Failure><Murine><Mus><Myeloid Differentiation-Inducing Protein><NADPH Oxidase><NETRIN 1-Like><NTN1><NTN1 gene><NTN1 gene product><NTN1L><Organ failure><Outbreaks><Outcome><Oxidation-Reduction><Oxidative Stress><P44ERK1><PRSS10><PSTkinase p44mpk><Pathogenesis><Pathologic><Pathologic Processes><Pathological Processes><Pathway interactions><Patients><Permeability><Physiopathology><Plasma Membrane><Plasmacytoma Growth Factor><Post-Menopause><Post-menopausal Period><Postmenopausal Period><Postmenopause><Production><Protein Isoforms><Proteins><Publications><Publishing><Pulmonary Edema><RNA Seq><RNA Sequences><RNA sequencing><RNAseq><Redox><Regulation><Reporting><Research><Respiratory Disease><Respiratory System Disease><Respiratory System Disorder><Role><SARS-CoV-2 S protein><SARS-CoV-2 infected patient><SARS-CoV-2 outbreak><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV2 S protein><SARS-CoV2 outbreak><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><SCYA2><Scientific Publication><Serine Endopeptidases><Serine Protease><Serine Protein Hydrolases><Serine Proteinases><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 outbreak><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severity of illness><Sex Differences><Sexual differences><Shock Lung><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Small Inducible Cytokine A2><Smoker><Smoking><Stiff lung><Structure of parenchyma of lung><Superoxide Anion><Superoxide Radical><Superoxides><Systems Biology><TMPRSS2><TMPRSS2 gene><Therapeutic><Therapeutic Estrogen><Time><Uncertainty><Up-Regulation><Upregulation><Viral><Viral Diseases><Viral Receptor><Virus Diseases><Virus Receptors><Weight><Woman><angiotensin converting enzyme 2><angiotensin converting enzyme II><biological signal transduction><calcium-dependent CaM kinase II><calmodulin-dependent protein kinase II><cell damage><cell injury><cell type><cellular damage><cigarette smoking><cigarette use><coronavirus disease 2019 S protein><coronavirus disease 2019 infected patient><coronavirus disease 2019 outbreak><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19 outbreak><coronavirus disease-19 patient><coronavirus patient><cytokine><cytokine release syndrome><cytokine storm><damage to cells><develop a vaccine><develop vaccines><development of a vaccine><developmental><disease severity><doubt><effective therapy><effective treatment><endothelial dysfunction><estrogen treatment><experiment><experimental research><experimental study><gender difference><gender-associated difference><gene network><injuries><injury to cells><interferon beta 2><lung edema><lung injury><male><men><men's><mortality><multiorgan failure><multiorgan injury><multiple organ system failure><necropsy><netrin-1><neutralizing antibody><new drug target><new drug treatments><new druggable target><new drugs><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><oxidation reduction reaction><p44 MAPK><pandemic><pandemic disease><pathophysiology><pathway><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><plasmalemma><post-menopausal><postmenopausal><postmortem><preservation><pulmonary><pulmonary damage><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><renal><respiratory><response><scRNA-seq><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><sex-dependent differences><sex-related differences><sex-specific differences><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><transcriptome sequencing><treated with estrogen><treatment with estrogen><vaccine development><viral infection><viral infection mechanism><virus infection><virus infection mechanism><virus-induced disease><wet lung>