Document text
Principal Investigator: Daniel Barber
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2022
Award: $238,324
Funding agency: National Institute of Allergy and Infectious Diseases
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has a spectrum of clinical outcomes, ranging from asymptomatic to fatal. There is a need to parse out the role of individual immune cell types and molecular pathways that contribute to effective control of viral infection in asymptomatic/mild disease and those leading to organ failure during severe coronavirus disease 2019 (COVID-19). Increased proinflammatory cytokines, deficient type I interferon (IFN) responses, and activation of inflammasomes, neutrophils, and monocytes/macrophages have all been associated with severe COVID-19. Coordinated activation of CD8+ and CD4+ T cells, T cell activation state, and antigen (Ag) specificity have all been linked to favorable outcomes of SARS-CoV-2 infection. Whereas neutralizing antibodies are clearly protective in immune hosts, T cell responses may also contribute to the protection provided by vaccination and natural infection.
Most studies of immune correlates of COVID-19 disease severity in humans have focused on sampling of peripheral blood. Nevertheless, some studies have observed infiltration of immune cells into the bronchoalveolar lavage (BAL) fluid, into postmortem lung tissue acquired from fatal COVID-19 cases, or from individuals undergoing medically necessary procedures. On autopsy, several reports have observed an unexpected lack of immune cells infiltrating into extrapulmonary tissues despite the presence of high levels of virus. These data highlight the importance of understanding the early host response in pulmonary and extrapulmonary tissues in the first few days after SARS-CoV-2 infection.
Animal models can be used to obtain a detailed understanding of the host response in infected tissues. Studies in SARS-CoV-2susceptible species provide insights into COVID-19 disease pathogenesis. For example, transgenic mouse strains expressing human angiotensin converting enzyme 2 (ACE2) (K18-hACE2), and mice induced to express hACE2 with viral vectors, are highly susceptible to SARS-CoV-2 infection. Syrian hamsters and ferrets are also moderately susceptible and shed infectious virus. On the other hand, species more resistant to SARS-CoV-2 induced disease are useful tools in examining mechanisms of efficient control of viral replication. Several nonhuman primate (NHP) species can be experimentally infected with SARS-CoV-2. Rhesus macaques, cynomolgus macaques, and African green monkeys typically develop mild symptoms after SARS-CoV-2 infection. SARS-CoV-2immune and SARS-CoV-2vaccinated rhesus macaques are protected from reinfection primarily by neutralizing antibodies and, to a lesser extent, anamnestic T cell responses. Thus, current NHP models are suitable for the study of protective host immune responses associated with mild SARS-CoV-2 infection, but not the mechanisms of pathogenesis during severe disease.
In this reporting period, we used the rhesus macaque model of mild COVID-19 to examine the (i) kinetics of lung inflammation using 18F-fluorodeoxyglucose (18FDG) positron emission tomography/computed tomography (PET/CT) imaging, (ii) innate immune responses using single-cell RNA sequencing (scRNAseq), and (iii) the tissue distribution of SARS-CoV-2specific T cell responses by flow cytometry. Our findings suggest that mild SARS-CoV-2 disease and efficient control of the infection are temporally correlated with activation of myeloid cells by type I IFN before the induction of Ag-specific T and B cell responses. Moreover, they reveal a strong propensity for Ag-specific T cell migration into the pulmonary compartment compared with other mucosal sites of infection.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ACE2><African Green Monkey><Animal Model><Animal Models and Related Studies><Anti-Viral Response><Antigens><Antiviral Response><Autopsy><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood monocyte><Body Tissues><Bronchoalveolar Lavage Fluid><CAT scan><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8><CD8B><CD8B1><CD8B1 gene><COVID disease severity><COVID severity><COVID-19><COVID-19 disease severity><COVID-19 infection><COVID-19 predisposition><COVID-19 severity><COVID-19 susceptibility><COVID-19 virus><COVID-19 vulnerability><COVID19><COVID19 disease severity><COVID19 infection><COVID19 severity><COVID19 virus><CT X Ray><CT Xray><CT imaging><CT scan><CV-19><CV19><Cell Body><Cell Locomotion><Cell Migration><Cell Movement><Cells><Cellular Migration><Cellular Motility><Chlorocebus aethiops><Chlorocebus sabaeus><Clinical><CoV-2><CoV2><Computed Tomographic Scintigraphy><Computed Tomography><Computerized Emission Tomography><Coronavirus disease 2019 predisposition><Coronavirus disease 2019 susceptibility><Coronavirus disease 2019 vulnerability><Crab-Eating Macaque><Crab-Eating Monkey><Cynomolgus Monkey><Cynomolgus macaque><Data><Disease><Disease Progression><Disorder><Drug or chemical Tissue Distribution><Emission-Computed Tomography><Experimental Models><FDG PET><Ferrets><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Goals><Golden Hamsters><Golden Syrian Hamsters><Green Monkey><Host resistance><Human><IFN><Image><Immune><Immune infiltrates><Immune response><Immune system><Immunes><Immunological response><Individual><Infection><Infection Control><Inflammasome><Innate Immune Response><Interferon Type I><Interferons><K-18><K-18 conjugate><K18><K18 combination><Kinetics><LYT3><Link><Lung><Lung Inflammation><Lung Parenchyma><Lung Respiratory System><Lung Tissue><Lung diseases><M fascicularis><M mulatta><M. fascicularis><M. mulatta><Macaca><Macaca fascicularis><Macaca mulatta><Macaque><Marrow Neutrophil><Marrow monocyte><Mesocricetus auratus><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Motility><Mouse Strains><Murine><Mus><Myeloid Cell Activation><Mφ><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Organ failure><Outcome><PET><PET Scan><PET imaging><PETSCAN><PETT><Pathogenesis><Pathology><Pathway interactions><Pneumonitis><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Positron Emission Tomography Medical Imaging><Positron Emission Tomography Scan><Positron-Emission Tomography><Predisposed to COVID-19><Predisposed to SARS-CoV-2><Predisposed to Severe acute respiratory syndrome coronavirus 2><Procedures><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Inflammation><Rad.-PET><Radionuclide CAT Scan><Receptor Protein><Regulation><Reporting><Resistance><Rhesus Macaque><Rhesus Monkey><Role><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS-Associated Coronavirus><SARS-CO-V2><SARS-COVID-2><SARS-CoV><SARS-CoV-1><SARS-CoV-2><SARS-CoV-2 disease severity><SARS-CoV-2 infection><SARS-CoV-2 predisposition><SARS-CoV-2 severity><SARS-CoV-2 susceptibility><SARS-CoV-2 vulnerability><SARS-CoV2><SARS-CoV2 infection><SARS-Related Coronavirus><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><Severe Acute Respiratory Coronavirus><Severe Acute Respiratory Coronavirus 2><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 Virus><Severe 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Cell><Type I Epithelial Receptor Cell><Vaccination><Viral Diseases><Viral Vector><Virus><Virus Diseases><Virus Replication><Wuhan coronavirus><X-Ray CAT Scan><X-Ray Computed Tomography><X-Ray Computerized Tomography><Xray CAT scan><Xray Computed Tomography><Xray computerized tomography><after COVID-19 infection><after SARS-CoV-2 infection><after SARS-CoV2 infection><after severe acute respiratory distress syndrome CoV-2 infection><allergic/immunologic body system><allergic/immunologic organ system><angiotensin converting enzyme 2><angiotensin converting enzyme II><antigen-specific T cells><catscan><cell imaging><cell motility><cell type><cellular imaging><computed axial tomography><computer tomography><computerized axial tomography><computerized tomography><confocal imaging><corona virus disease 2019><coronavirus disease 2019><coronavirus disease 2019 disease severity><coronavirus disease 2019 infection><coronavirus disease 2019 severity><coronavirus disease 2019 virus><coronavirus 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2019><life-threatening severe acute respiratory syndrome coronavirus 2><lung disorder><macrophage><medically necessary><medically necessary care><model of animal><model organism><monocyte><mucosal site><nCoV2><necropsy><neutralizing antibody><neutrophil><non-contrast CT><non-human primate><noncontrast CT><noncontrast computed tomography><nonhuman primate><pathway><peripheral blood><positron emission tomographic (PET) imaging><positron emission tomographic imaging><positron emitting tomography><post SARS-CoV-2 infection><postmortem><predisposed to Coronavirus disease 2019><previous COVID-19 infection><previous SARS-CoV-2 infection><previous SARS-CoV2 infection><previous severe acute respiratory distress syndrome CoV-2 infection><prior COVID-19 infection><prior SARS-CoV-2 infection><prior SARS-CoV2 infection><prior severe acute respiratory distress syndrome CoV-2 infection><pulmonary><radionuclide emission tomography><receptor><resistant><response><scRNA-seq><serious COVID><serious 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