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Principal Investigator: PAUL JOSEPH UTZ
Organization: STANFORD UNIVERSITY
Fiscal Year: 2021
Award: $158,000
Funding agency: National Institute of Allergy and Infectious Diseases
7. Project Summary/Abstract
The overarching goal of this New Aim 4 is to test the hypothesis that SARS-CoV-2 (CoV-2) causes autoimmune
disease (AI) in a subset of infected patients. Our preliminary studies on 336 COVID-19 samples from 282 COVID19 patients (four COVID-19 cohorts in three geographically distinct regions) have identified autoantibodies and
clinical evidence of AI. To test the hypothesis that autoantibodies develop following CoV-2 infection, we will use
autoantigen arrays to identify proteins targeted by autoantibodies, some of which may cause pathogenic
inflammatory responses that could mediate lung, skin, and other tissue injury, dysregulated coagulation,
endothelial dysfunction, and vasculopathy. We will then test the hypothesis that autoantibodies develop through
different mechanisms including molecular mimicry and generation of receptor-blocking anti-cytokine antibodies
(ACA) in response to “cytokine storm”. We hypothesize that infection with CoV-2 induces 2 different outcomes:
(i) the desired outcome - protective responses that neutralize CoV-2; or (ii) pathogenic responses that lead to
symptomatic autoimmunity or autoinflammatory disease. Aim 4.1 will test the hypothesis that CoV-2 causes
development of autoantibodies and classifiable autoimmune diseases by leveraging our custom “COVID-19
Autoantigen Array” comprising common autoantigens from diseases that affect the lung, endothelium and skin.
Aim 4.2 will characterize serum antibodies specific for proteins from CoV-2 and other coronaviruses, and
correlate with autoantibodies in Aim 1, by using our “COVID-19 Viral Array” capable of simultaneously
quantitating antibodies against many different wild-type and mutant viral proteins and peptides. Viral responses
will be correlated with clinical outcomes including development of autoantibodies, and progression to clinical
autoimmunity. Aim 4.3 will test the hypothesis that CoV-2 causes autoimmunity through mechanisms including
cross-reactivity (molecular mimicry) and cytokine storm which generates receptor-blocking ACA. We will use a
variety of lab-based techniques to explore these mechanisms, including purification of antigen-specific IgG from
serum, co-immunoprecipitation, and cross-binding assays. Together, the proposed experiments will begin to
quantify the impact of CoV-2 on AI, identify which antigens and specific AI are associated with CoV-2, and
contribute to our mechanistic understanding of COVID-19 pathogenesis, setting the stage for large-scale
epidemiology studies to determine the extent of autoimmunity that results from CoV-2 infection, as well as longterm impacts on the health care system and economy.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><7S Gamma Globulin><ATAC-seq><ATACseq><Affect><Aging><Anti-Australia Antigens><Anti-HBAg><Anti-Hepatitis B Antigens><Antibodies><Antigens><Assay><Autoantibodies><Autoantigens><Autoimmune Diseases><Autoimmune Status><Autoimmunity><Autologous Antigens><B cell repertoire><Big Data><BigData><Binding><Bio-Informatics><Bioassay><Bioinformatics><Biologic Assays><Biological><Biological Assay><Biological Function><Biological Markers><Biological Process><Biology><Blood Plasma><Blood Sample><Blood Serum><Blood specimen><CEB1 Gene><COVID infected patient><COVID patient><COVID positive patient><COVID-19><COVID-19 infected patient><COVID-19 pathogenesis><COVID-19 patient><COVID-19 positive patient><COVID-19 virus><COVID19><COVID19 pathogenesis><COVID19 patient><COVID19 positive patient><COVID19 virus><CV-19><CV19><Cell Communication and Signaling><Cell Signaling><Cell 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Pathway><Infectious Diseases><Infectious Disorder><Inflammatory Response><Influenza><Influenza Vaccines><Influenza immunization><Influenza vaccination><Intracellular Communication and Signaling><LOC51191><LY6E><LY6E gene><LY6E protein><Lead><Lung><Lung Respiratory System><Lymphocyte Antigen 6 Complex, Locus E><Measurement><Measures><Mediating><Messenger RNA><Microfluidics><Modern Man><Molecular Interaction><Molecular Mimicry><NIAID><National Institute of Allergy and Infectious Disease><Non-Polyadenylated RNA><Outcome><Pathogenicity><Pathway interactions><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Pb element><Peptides><Plasma><Plasma Serum><Prophylactic vaccination against influenza><Proteins><RIG-E><RIGE><RIGE Thymic Shared Antigen 1><RNA><RNA Gene Products><RNA Seq><RNA sequencing><RNAseq><Receptor Protein><Recovery><Research><Reticuloendothelial System, Serum, Plasma><Retinoic Acid-Induced Gene E><Ribonucleic Acid><SARS corona virus 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therapy target><outcome following vaccination><outcome following vaccine><pathogen><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><predicting response><prediction of response><predictive biomarkers><predictive marker><predictive molecular biomarker><predictive response><predictive signature><predictor of response><priority pathogen><pulmonary><receptor><response><response prediction><result following vaccination><result following vaccine><rural locality><rural place><rural setting><seasonal flu><seasonal influenza><self reactive antibody><sensor><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><thymus derived lymphocyte><tissue injury><transcriptome sequencing><vaccination against influenza><vaccination outcome><vaccination result><vaccination study><vaccination trial><vaccine against flu><vaccine against influenza><vaccine outcome><vaccine response><vaccine result><vaccine study><vaccine trial><vascular dysfunction><vasculopathy><viral infection><virus infection><virus protein><virus-induced disease><µfluidic>