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Principal Investigator: Florian Douam
Organization: BOSTON UNIVERSITY MEDICAL CAMPUS
Fiscal Year: 2021
Award: $242,950
Funding agency: National Institute of Environmental Health Sciences
Project Summary
We are in the midst of an unprecedented, modern pandemic as a result of the evolution of the novel severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019. SARS-CoV-2 is one of three known
coronaviruses that can replicate in the lower respiratory tract and cause pneumonia and acute respiratory
distress syndrome, which can be fatal. However, people are not equally susceptible to development of severe
SARS-CoV-2 infection disease (COVID-19). Some risk factors are known, including male sex and
comorbidities related to metabolic disease. This pandemic has occurred during an endemic exposure to a
class of chemicals called per- and polyfluoroalkyl substances (PFAS) in the United States. Daily exposures
occur via PFAS contaminated food, drinking water, dust and air, resulting in nearly universal detection in
people examined. What we do not know is how PFAS exposure may influence susceptibility to SARS-CoV-2
infection and COVID-19. SARS-CoV-2 infects airway epithelial cells, triggering a Th1-polarizing pro-
inflammatory response. Resolution of the infection is driven by CD8+ T cell-mediated clearance of infected cells
and inactivation of the free virus by antibody-binding. Disease severity is associated with lymphopenia and
reduced IFN-γ production by CD4+ T cells. PFAS are well-known immunosuppressive agents in rodent models,
and PFAS are associated with reduced antibody titers following vaccinations in humans. Our data, and others,
show that PFAS are agonists for nuclear receptors, including peroxisome proliferator activated receptor α
(PPARα), constitutive androstane receptor (CAR) and pregnane X receptor (PXR) and that their respective
transcriptional programs are upregulated following in vivo exposure. Intriguingly, activation of at least PPARα
and PXR in T cells results in Th2-skewing, reduced IFN-γ production, and lymphopenia. Here, we propose to
examine the interaction between exposure to legacy (perfluorooctanoic acid, PFOA) and replacement
(perfluoro(2-methyl-3-oxahexanoic) acid, GenX) PFAS and infection with SARS-CoV-2. We will test the
hypothesis that PFAS exposure enhances susceptibility to SARS-CoV-2 infection via interaction with nuclear
receptors. First, there are critical, species-specific differences in proteins regulating susceptibility to SARS-
CoV-2 infection (angiotensin-converting enzyme 2 (ACE2)) and the biological effects of PFAS (PPARα). In Aim
1 we will generate a novel hACE2/hPPARα transgenic mouse and examine the effects of SARS-CoV-2
infection in mice with human relevant steady-state body burdens of PFAS. Second, efficient CD4+ T cell
function is essential for minimizing risk of developing COVID-19. PFAS activate multiple nuclear receptors
known to regulate immune function and T cell function. In Aim 2, we will use adeno-associated virus-mediated
transduction of PPARα, CAR and PXR shRNA in vivo, to test the necessity for each receptor in enhancing
susceptibility to SARS-CoV-2 and how PFOA’s effects are modified. The results will provide essential
information on how concurrent exposures to environmental chemicals enhance the risk of severe COVID-19.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ACE2><ARDS><Acids><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Address><Adeno-Associated Viruses><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Agonist><Air><American><Antibodies><Antibody titer measurement><Apoptosis><Apoptosis Pathway><Binding><Biological><Body Burden><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><COVID><COVID disease severity><COVID severity><COVID-19><COVID-19 disease severity><COVID-19 infection><COVID-19 severity><COVID-19 virus><COVID19><COVID19 disease severity><COVID19 infection><COVID19 severity><COVID19 virus><CV-19><CV19><Cardiovascular Diseases><Cell Body><Cell Function><Cell Process><Cell physiology><Cells><Cellular Function><Cellular Immune Function><Cellular Physiology><Cellular Process><Chemicals><CoV disease><CoV-2><CoV2><Coronaviridae><Coronavirus><Da Nang Lung><Data><Dependoparvovirus><Dependovirus><Detection><Development><Diabetes Mellitus><Diet><Disease><Disorder><Dust><Environment><Epithelial Cells><Evolution><Exposure to><Fire - disasters><Fires><Food><Food Contamination><Food or Food Product><Gamma interferon><Gene Transcription><Generations><Genetic Transcription><Human><Hydrogen Oxide><Hypertension><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><Immune Interferon><Immune response><Immune system><Immunological response><Immunosuppressants><Immunosuppression><Immunosuppression Effect><Immunosuppressive Agents><Immunosuppressive Effect><Immunosuppressive drug><Immunosuppressive treatment><Infection><Inflammatory><Inflammatory Response><Interferon Gamma><Interferon Type II><Interferon-gamma><K-18><K-18 conjugate><K18><K18 combination><Lower respiratory tract structure><Lung Alveolar Epithelia><Lymphocytopenia><Lymphopenia><Mediating><Metabolic><Metabolic Diseases><Metabolic Disorder><Metabolic dysfunction><Mice><Mice Mammals><Modeling><Modern Man><Modernization><Molecular Interaction><Murine><Mus><Mφ><Nuclear Receptors><PPAR alpha><PPAR-α><PPARalpha><PPARα><PXR receptor><Paint><Patients><Peroxisome Proliferator-Activated Receptor alpha><Peroxisome Proliferator-Activated Receptor α><Pneumonia><Polishes><Predisposition><Production><Prognosis><Programmed Cell Death><Propionic Acids><Proteins><RNA Expression><Receptor Protein><Research Resources><Resolution><Resources><Risk><Risk Factors><Rodent Model><Role><SARS corona virus 2><SARS-CoV-2><SARS-CoV-2 disease severity><SARS-CoV-2 infection><SARS-CoV-2 severity><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><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 corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome related corona virus 2><Severity of illness><Shock Lung><Staining method><Stains><Stiff lung><Subcellular Process><Susceptibility><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><Testing><Textiles><Thesaurismosis><Transcription><Transgenic Mice><United States><Vaccination><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Virus><Water><Waxes><Work><Wuhan coronavirus><adeno associated virus group><airway epithelium><allergic/immunologic body system><allergic/immunologic organ system><alveolar epithelium><angiotensin converting enzyme 2><angiotensin converting enzyme II><antibody titering><cardiovascular disorder><co-morbid><co-morbidity><comorbidity><constitutive androstane receptor><consumer product><contaminated food><corona virus><corona virus disease><corona virus disease 2019><coronavirus disease><coronavirus disease 2019><coronavirus disease 2019 disease severity><coronavirus disease 2019 infection><coronavirus disease 2019 severity><coronavirus disease 2019 virus><coronavirus disease severity><cost><cytokine><cytokine release syndrome><cytokine storm><developmental><diabetes><diets><disease severity><drinking water><environmental chemical><experience><fabric><fighting><fire><hCoV19><high blood pressure><host response><humanized mice><humanized mouse><hyperpiesia><hyperpiesis><hypertensive disease><immune function><immune suppression><immune suppressive agent><immune suppressor><immune system response><immunoresponse><immunosuppressive substance><immunosuppressor><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><lFN-Gamma><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><lower respiratory tract><macrophage><male><metabolism disorder><mouse model><murine model><nCoV2><novel><pandemic><pandemic disease><perfluorooctanoate><perfluorooctanoic acid><pregnane X receptor><programs><propanoic acid><receptor><risk minimization><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 disease severity><severe acute respiratory syndrome coronavirus 2 severity><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><sex><shRNA><short hairpin RNA><small hairpin RNA><social role><thymus derived lymphocyte><wet lung>