Document text
Principal Investigator: Daniel Barber
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2023
Award: $163,023
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.
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><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 associated death><COVID-19 associated fatality><COVID-19 associated mortality><COVID-19 death><COVID-19 disease severity><COVID-19 fatality><COVID-19 induced death><COVID-19 induced fatality><COVID-19 induced mortality><COVID-19 infection><COVID-19 mortality><COVID-19 predisposition><COVID-19 related death><COVID-19 related fatality><COVID-19 related mortality><COVID-19 severity><COVID-19 susceptibility><COVID-19 virus><COVID-19 virus infection><COVID-19 vulnerability><COVID19><COVID19 associated death><COVID19 associated fatality><COVID19 associated mortality><COVID19 death><COVID19 disease severity><COVID19 fatality><COVID19 induced death><COVID19 induced fatality><COVID19 induced mortality><COVID19 infection><COVID19 mortality><COVID19 related death><COVID19 related fatality><COVID19 related mortality><COVID19 severity><COVID19 virus><CT X Ray><CT Xray><CT imaging><CT scan><CV-19><CV19><Chlorocebus aethiops><Chlorocebus sabaeus><Clinical><CoV-2><CoV2><Computed 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><Experimental Models><Ferrets><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Goals><Golden Hamsters><Golden Syrian Hamsters><Green Monkey><Host resistance><Human><Immune><Immune infiltrates><Immune response><Immune system><Immunes><Immunological response><Individual><Infection><Infection Control><Inflammasome><Inflammatory><Interferon Type I><K-18><K-18 conjugate><K18><K18 combination><LYT3><Link><Lung><Lung Parenchyma><Lung Respiratory System><Lung Tissue><Lung diseases><M fascicularis><M mulatta><M. fascicularis><M. mulatta><Macaca><Macaca fascicularis><Macaca mulatta><Macaque><Macrophage><Marrow Neutrophil><Marrow monocyte><Mesocricetus auratus><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Mouse Strains><Murine><Mus><Mφ><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Organ failure><Outcome><PET/CT><PET/CT scan><Pathogenesis><Pathology><Pathway interactions><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Predisposed to COVID-19><Predisposed to SARS-CoV-2><Predisposed to Severe acute respiratory syndrome coronavirus 2><Predisposition><Procedures><Pulmonary Diseases><Pulmonary Disorder><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 associated death><SARS-CoV-2 associated fatality><SARS-CoV-2 associated mortality><SARS-CoV-2 death><SARS-CoV-2 disease severity><SARS-CoV-2 fatality><SARS-CoV-2 induced death><SARS-CoV-2 induced fatality><SARS-CoV-2 induced mortality><SARS-CoV-2 infection><SARS-CoV-2 mortality><SARS-CoV-2 predisposition><SARS-CoV-2 related death><SARS-CoV-2 related fatality><SARS-CoV-2 related mortality><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 Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><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 coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 predisposition><Severe acute respiratory syndrome coronavirus 2 susceptibility><Severe acute respiratory syndrome coronavirus 2 vulnerability><Severe acute respiratory syndrome related corona virus 2><Specificity><Structure of parenchyma of lung><Susceptibility><Symptoms><Syrian Hamsters><T cell response><T-Cell Activation><T-Cell Subsets><T-Lymphocyte Subsets><T4 Cells><T4 Lymphocytes><Tissues><Tomodensitometry><Transgenic Mice><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><activate T cells><after COVID-19 infection><after SARS-CoV-2 infection><after SARS-CoV2 infection><after infection by SARS-CoV-2><after severe acute respiratory distress syndrome CoV-2 infection><angiotensin converting enzyme 2><angiotensin converting enzyme II><catscan><cell imaging><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 associated death><coronavirus disease 2019 associated fatality><coronavirus disease 2019 associated mortality><coronavirus disease 2019 death><coronavirus disease 2019 disease severity><coronavirus disease 2019 fatality><coronavirus disease 2019 induced death><coronavirus disease 2019 induced fatality><coronavirus disease 2019 induced mortality><coronavirus disease 2019 infection><coronavirus disease 2019 mortality><coronavirus disease 2019 related death><coronavirus disease 2019 related fatality><coronavirus disease 2019 related mortality><coronavirus disease 2019 severity><coronavirus disease 2019 virus><coronavirus disease severity><coronavirus disease-19><coronavirus disease-19 mortality><coronavirus disease-19 virus><coronavirus infectious disease-19><cytokine><death due to COVID-19><death due to COVID19><death due to SARS-CoV-2><death due to coronavirus disease 2019><death due to severe acute respiratory syndrome coronavirus 2><death in COVID><death in COVID-19><death in SARS-CoV-2><death in coronavirus disease><death in coronavirus disease 2019><death in severe acute respiratory syndrome coronavirus 2><disease of the lung><disorder of the lung><experiment><experimental research><experimental study><experiments><fatality due to COVID-19><fatality due to COVID19><fatality due to SARS-CoV-2><fatality due to coronavirus disease 2019><fatality due to severe acute respiratory syndrome coronavirus 2><flow cytophotometry><following COVID-19 infection><following SARS-CoV-2 infection><following SARS-CoV2 infection><following infection by SARS-CoV-2><following severe acute respiratory distress syndrome CoV-2 infection><hCoV19><host response><immune cell infiltrate><immune system response><immunogen><immunoresponse><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><insight><interest><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 disorder><medically necessary><medically necessary care><model of animal><monocyte><mortality due to COVID-19><mortality due to COVID19><mortality due to SARS-CoV-2><mortality due to coronavirus disease 2019><mortality due to severe acute respiratory syndrome coronavirus 2><nCoV2><necropsy><neutralizing antibody><neutrophil><non-contrast CT><non-human primate><noncontrast CT><noncontrast computed tomography><nonhuman primate><pathway><peripheral blood><positron emission computed 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><receptor><resistant><response><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 associated death><severe acute respiratory syndrome coronavirus 2 associated fatality><severe acute respiratory syndrome coronavirus 2 associated mortality><severe acute respiratory syndrome coronavirus 2 death><severe acute respiratory syndrome coronavirus 2 disease severity><severe acute respiratory syndrome coronavirus 2 fatality><severe acute respiratory syndrome coronavirus 2 induced death><severe acute respiratory syndrome coronavirus 2 induced fatality><severe acute respiratory syndrome coronavirus 2 induced mortality><severe acute respiratory syndrome coronavirus 2 mortality><severe acute respiratory syndrome 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