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Principal Investigator: ROBERTO G BACCALA
Organization: SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE
Fiscal Year: 2021
Award: $423,965
Funding agency: National Institute of Environmental Health Sciences
Project Summary
COVID-19 caused by the novel coronavirus SARS-Cov-2 first emerged in December 2019 and was officially
declared a pandemic by WHO in March 2020. During this time, COVID-19 has caused millions of cases and
deaths across the world. While most cases are asymptomatic or present with mild respiratory and flu-like
symptoms, a significant fraction of COVID-19 patients develop severe pulmonary complications,
overproduction of inflammatory factors and other manifestations, leading in critical cases to multiorgan
dysfunction, respiratory failure and death. Strikingly, recent evidence indicates that, besides the typical
severe lung pathology, SARS-Cov-2 infection also promotes autoantibody production and other autoimmune
manifestations in some patients. However, why other patients seem protected and the mechanisms for
COVID-19-associated autoimmunity remain unknown. We hypothesize that autoimmunity development in
SARS-Cov-2-infected patients depends on genetic predisposition but also on the history of the individual’s
exposure to environmental triggers, including crystalline silica, an abundant mineral often associated with
autoimmunity. To test this possibility, in this supplemental application we propose experiments with mice
expressing human ACE2, the receptor for SARS-Cov-2. These mice will be infected with SARS-Cov-2 at
doses that induce low-level COVID-related pathology but no mortality, allowing long-term monitoring for
autoimmunity. We will test the effect of the time of SARS-Cov-2 infection and airway exposure to crystalline
silica on autoimmune manifestations in hACE2-expressing non-autoimmune and lupus-prone mouse models.
In addition, we will examine how the dose of silica affects induction of autoimmunity in SARS-Cov-2-infected
mice. The results will provide proof of concept that exposure to environmental agents may exacerbate
COVID-19-associated inflammatory and autoimmune responses, creating the foundation for future studies to
assess the effect of other environmental triggers, mechanisms of disease pathogenesis, and potential
therapeutic interventions.
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emergence><CoV-2><CoV2><Complication><Coronaviridae><Coronavirus><Cristobalite><Death><Development><Diathesis><Disease><Disease susceptibility><Disorder><Dose><Dysfunction><Environment><Environmental Factor><Environmental Risk Factor><Epidemiology><Exposure to><Fibrosis><Foundations><Functional disorder><Future><General Population><General Public><Genetic><Genetic Predisposition><Genetic Predisposition to Disease><Genetic Susceptibility><History><Human><Individual><Infection><Inflammation><Inflammatory><Inflammatory Response><Inhalation><Inhaling><Inherited Predisposition><Inherited Susceptibility><LCM Viruses><LCMV><Lung><Lung Respiratory System><Lung diseases><Lupus Erythematosus Disseminatus><Lymphocytic choriomeningitis virus><Mice><Mice Mammals><Minerals><Modeling><Modern Man><Monitor><Murine><Mus><Parents><Pathogenesis><Pathology><Patients><Physiopathology><Predisposition><Production><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Pathology><Receptor Protein><Recording of previous events><Resistance><Respiratory Disease><Respiratory Failure><Respiratory System Disease><Respiratory System Disorder><Role><SARS corona virus 2><SARS-CoV-2><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 pandemic><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV2><SARS-CoV2 epidemic><SARS-CoV2 infection><SARS-CoV2 pandemic><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SLE><Sand><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 CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><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 epidemic><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Silica><Silicon Dioxide><Silicosis><Soil><Susceptibility><Symptoms><System><Systemic Lupus Erythematosus><Systemic Lupus Erythematous><Systemic Lupus Erythmatosus><Testing><Therapeutic Intervention><Time><Tissues><Tridymite><Viral Diseases><Viral Genetics><Virus><Virus Diseases><Wuhan coronavirus><angiotensin converting enzyme 2><angiotensin converting enzyme II><autoimmune antibody><autoimmune condition><autoimmune disorder><autoreactive antibody><corona virus><corona virus disease><corona virus disease 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virus><emergent coronavirus><emerging CoV><emerging corona virus><emerging coronavirus><environmental agent><environmental risk><epidemiologic><epidemiological><experiment><experimental research><experimental study><flu><genetic etiology><genetic mechanism of disease><genetic vulnerability><genetically predisposed><hCoV19><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><liability to disease><lung disorder><lung failure><lung pathology><lupus prone mice><mortality><mouse model><murine model><nCoV><nCoV2><new CoV><new corona virus><new coronavirus><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><novel CoV><novel corona virus><novel coronavirus><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><pandemic><pandemic disease><pathophysiology><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><pulmonary><pulmonary failure><receptor><resistant><respiratory><self reactive antibody><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><social role><synergism><systemic autoimmunity><systemic lupus erythematosis><viral infection><virus genetics><virus infection><virus-induced disease>