Document text
Principal Investigator: Megan A O'Connor
Organization: UNIVERSITY OF WASHINGTON
Fiscal Year: 2023
Award: $815,811
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY/ABSTRACT
COVID-19 vaccination reduces the risk of SARS-CoV-2 infection and severe disease, but almost half of
hospitalized breakthrough cases are in immunocompromised individuals. HIV infection is an independent risk
factor for severe COVID-19, hospitalization, and mortality. Immunocompromised individuals are more likely to
have prolonged SARS-CoV-2 infection and viral shedding, increasing the risk of viral transmission and allowing
for rapid evolution of more virulent strains. Therefore, investigating SARS-CoV-2 pathogenesis in the context of
immunosuppression is urgently needed to reveal factors driving severe COVID-19. SARS-CoV-2 lung
pathogenesis is characterized by infiltration of innate and adaptive immune cells into the lung and induction of
an inflammatory immune response. Similar mechanisms of inflammation and immune dysfunction during HIV
infection contribute to systemic HIV pathogenesis and lung pathology. Therefore, dysregulation of immune
responses during HIV infection could induce severe disease outcomes during SARS-CoV-2 coinfection. SARS-
CoV-2 replication occurs in both respiratory and gastrointestinal mucosal sites and enteric symptoms are
associated with COVID-19. There is a defined link between gastrointestinal microbial dysbiosis with accelerated
HIV disease progression and an emerging role of lung and intestinal microbial dysbiosis with severe COVID-19.
Given that the microbiome plays an important role in maintaining mucosal function and homeostasis, shifts in
microbial communities due to HIV infection could contribute to inflammation and immune activation that would
drive exacerbated SARS-CoV-2 pathogenesis. Here, we will test the hypothesis that increased immune
dysfunction and exhaustion, inflammation, and microbial dysbiosis during HIV infection promote enhanced
SARS-CoV-2 lung pathogenesis. We will leverage the pigtail macaque simian immunodeficiency virus (SIV)
model of rapid HIV/AIDS and will test this hypothesis during a state of inflammatory untreated SIV infection and
during primary and secondary SARS-CoV-2 viral challenges. We will evaluate the roles of SIV-induced
immunosuppression and altered alveolar macrophage and neutrophil function on SARS-CoV-2 pathogenesis
and pulmonary pathology. We will determine whether HIV infection causes gastrointestinal tract and lung
microbial dysbiosis and its association with SARS-CoV-2 disease severity. Lastly, we will determine whether
increased immune exhaustion during HIV infection promotes deficits in the generation of primary anti-viral SARS-
CoV-2 responses that impairs protection from heterologous SAR-CoV-2 re-challenge. These studies will
contribute to our understanding of how normal immunity drives SARS-CoV-2 lung pathophysiology and will
dissect how perturbations of immune responses during HIV infection contribute to enhanced disease.
Terms: <16S gene sequencing><16S rRNA amplicon sequencing><16S rRNA gene amplicon sequencing><16S rRNA gene sequencing><16S rRNA genomic profiling><16S rRNA sequencing><16S ribosomal RNA gene sequencing><16S ribosomal RNA sequencing><16S sequencing><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV variant><2019-nCoV variant forms><2019-nCoV variant strains><ACE2><AIDS Virus><AIDS/HIV><Acceleration><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Acute><Affect><Alimentary Canal><Alveolar Macrophages><Animals><Automobile Driving><Autoregulation><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood monocyte><COVID disease severity><COVID severity><COVID-19><COVID-19 anti-viral><COVID-19 antiviral><COVID-19 disease severity><COVID-19 infection><COVID-19 prevention><COVID-19 severity><COVID-19 vaccination><COVID-19 variant><COVID-19 variant forms><COVID-19 variant strains><COVID-19 virus><COVID-19 virus infection><COVID19><COVID19 disease severity><COVID19 infection><COVID19 prevention><COVID19 severity><COVID19 vaccination><COVID19 virus><CV-19><CV19><Cell Body><Cells><Cessation of life><CoV-2><CoV2><Death><Digestive Tract><Disease><Disease Outcome><Disease Progression><Disorder><Dysfunction><Enteral><Enteric><Enterocytes><Epithelial Cells><Evolution><Frequencies><Functional disorder><GI Tract><Gastrointestinal Tract><Gastrointestinal tract structure><Generations><HIV><HIV Infections><HIV/AIDS><HTLV-III Infections><HTLV-III-LAV Infections><Homeostasis><Hospital Admission><Hospitalization><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Humoral Immunities><Immune><Immune Cell Activation><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immune response><Immunes><Immunity><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunodeficiency Disorder><Immunodeficiency Syndrome><Immunodeficiency and Immunosuppression Disorders><Immunologic Deficiency Syndromes><Immunologic Diseases><Immunological Deficiency Syndromes><Immunological Diseases><Immunological Dysfunction><Immunological System Dysfunction><Immunological response><Immunosuppressed Host><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Impairment><Individual><Infiltration><Inflammation><Inflammatory><Inflammatory Response><Innate Immune Response><Intestinal><Intestines><LAV-HTLV-III><Link><Lung><Lung Inflammation><Lung Respiratory System><Lymphadenopathy-Associated Virus><M nemestrina><M. nemestrina><Macaca nemestrina><Macrophage><Marrow Neutrophil><Marrow monocyte><Measures><Modeling><Mucosa><Mucosal Tissue><Mucous Membrane><Mφ><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Outcome><Pathogenesis><Pathologic><Persons><Phase><Physiological Homeostasis><Physiopathology><Pigtail Macaque><Pigtail Monkey><Play><Pneumonitis><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Proteobacteria><Pulmonary Body System><Pulmonary Inflammation><Pulmonary Macrophages><Pulmonary Organ System><Pulmonary Pathology><Purple Bacteria><Receptor Protein><Rectum><Respiratory System><Respiratory Tracts><Respiratory tract structure><Risk><Risk Factors><Risk Reduction><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 anti-viral><SARS-CoV-2 antiviral><SARS-CoV-2 disease severity><SARS-CoV-2 infection><SARS-CoV-2 pathogenesis><SARS-CoV-2 severity><SARS-CoV-2 vaccination><SARS-CoV-2 variant><SARS-CoV-2 variant forms><SARS-CoV-2 variant strains><SARS-CoV2><SARS-CoV2 anti-viral><SARS-CoV2 antiviral><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related 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immunity><alimentary tract><anal microbiome><angiotensin converting enzyme 2><angiotensin converting enzyme II><anti-viral development><anti-viral drug development><anti-viral therapeutic development><anti-viral therapy development><antibody-based immunity><antiviral development><antiviral drug development><antiviral therapeutic development><antiviral therapy development><associated symptom><bowel><co-infection><co-morbid><co-morbid symptom><co-morbidity><co-occuring symptom><coinfection><community microbes><comorbid symptom><comorbidity><concurrent symptom><cooccuring symptom><corona virus disease 2019><coronavirus disease 2019><coronavirus disease 2019 anti-viral><coronavirus disease 2019 antiviral><coronavirus disease 2019 disease severity><coronavirus disease 2019 infection><coronavirus disease 2019 prevention><coronavirus disease 2019 severity><coronavirus disease 2019 vaccination><coronavirus disease 2019 variant><coronavirus disease 2019 variant forms><coronavirus disease 2019 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COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><innovate><innovation><innovative><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 microbiome><lung pathology><microbial><microbial community><microbial imbalance><microbiome><microbiome community composition><microbiome composition><microbiome species composition><monocyte><mortality><mucosal site><nCoV2><neutrophil><non-human primate><nonhuman primate><oral commensal><pathophysiology><pig-tailed macaque><prevent COVID-19><prevent COVID19><prevent coronavirus disease 2019><pulmonary><pulmonary microbiome><receptor><rectal><rectal microbiome><rectum microbiome><reduce risk><reduce risks><reduce that risk><reduce the risk><reduce these risks><reduces risk><reduces the risk><reducing risk><reducing the risk><respiratory><respiratory pathogen><response><risk-reducing><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 anti-viral><severe acute respiratory syndrome coronavirus 2 antiviral><severe acute respiratory syndrome coronavirus 2 disease severity><severe acute respiratory syndrome coronavirus 2 pathogenesis><severe acute respiratory syndrome coronavirus 2 severity><severe acute respiratory syndrome coronavirus 2 variant><severe acute respiratory syndrome coronavirus 2 variant forms><severe acute respiratory syndrome coronavirus 2 variant strains><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><social role><symptom association><symptom comorbidity><vaccinate against COVID-19><vaccinate against COVID19><vaccinate against SARS-CoV-2><vaccinate against coronavirus disease 2019><vaccinate against severe acute respiratory syndrome coronavirus 2><vaccination against COVID-19><vaccination against COVID19><vaccination against SARS-CoV-2><vaccination against Severe acute respiratory syndrome coronavirus 2><vaccination against coronavirus disease 2019><variants of concern><viral infection><viral transmission><virus infection><virus transmission><virus-induced disease>