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Principal Investigator: RAYMOND T CHUNG
Organization: MASSACHUSETTS GENERAL HOSPITAL
Fiscal Year: 2024
Award: $2,446,152
Funding agency: National Institute of Allergy and Infectious Diseases
Program Summary
While we have learned a tremendous amount about human immune responses in recent years, many studies of
human immunology examine the system in a static state of health or disease. However, to truly define how a
complex system works, dissect the components that interact with each other under dynamic conditions, and gain
actionable knowledge of how the system effectively resets (or not) during and after disease, the system must be
perturbed. Thus, the central theme of this Program is that by capturing perturbations of the human
immune system and performing high resolution studies of key immune cell types and immune reactions
in flux we will gain new mechanistic insights into the functional connections driving productive or
pathological immune responses in humans. To address this central theme, we propose 3 Projects to: 1) test
the hypothesis that post acute sequelae of COVID-19 (PASC) is associated with incomplete clearance of SARS-
CoV-2 and/or reactivation of latent viruses, resulting in chronic inflammation and durable immune dysregulation;
2) utilize chronic and cured HCV infection as a human model system for defining the impact of both natural and
precision immune perturbation on overall host fitness and health; and 3) define mechanisms of human vaccine-
induced immune memory using precision immune perturbation through PD-1 pathway blockade. Each Project
captures a key immune perturbation with a major common feature of known timing and nature of the perturbation
including viral infection leading to PASC (Project 1), viral cure in a long-standing chronic infection (Project 2),
and vaccination in the context of precision disruption of a single immune pathway, PD-1 (Project 3). As a result,
we “capture the human experiment” through focused profiling of the human immune system around these key
perturbations. These Projects are supported by an administrative Core and two scientific Cores that enable
robust human cohort development, management and sample collection (Core B) and high dimensional, highly
standardized, large scale and integrated immune landscape profiling for all patients and subjects studied (Core
C). This latter effort will allow common themes, immunotypes and cross-disease immune mechanisms to be
identified and leverages the interactions across our interconnected Projects. Thus, this highly interactive IPSG
CCHI U19 Program will allow us to make major mechanistic advances in our understanding of human antiviral
immunity.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Acute><Address><Antigens><Automobile Driving><Biologic Models><Biological Models><Blood><Blood Reticuloendothelial System><Body Tissues><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><COVID-19><COVID-19 virus><COVID19 virus><CV-19><Cell Body><Cells><Chronic><Chronic Disease><Chronic Hepatitis C><Chronic Illness><Chronic type C viral hepatitis><Chronic viral hepatitis C><Cicatrix><Clinical><CoV-2><CoV2><Communicable Diseases><Complex><Coronavirus Infectious Disease 2019><Data Base Management><Data Base Management Systems><Database Management Systems><Defect><Development><Disease><Disorder><FNA><Fine Needle Aspirate><Fine needle aspiration biopsy><Fine-Needle Aspiration><Fingerprint><Foundations><Goals><HCV><HCV infection><Health><Hepatitis C><Hepatitis C virus><Hepatitis C virus infection><Hepatitis, Viral, Non-A, Non-B, Parenterally-Transmitted><Hepatitus C><Human><IRB><IRBs><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 mediated therapy><Immune memory><Immune reaction><Immune response><Immune system><Immunes><Immunity><Immunodeficiency and Immunosuppression Disorders><Immunologic Diseases><Immunologic Memory><Immunological Diseases><Immunological Dysfunction><Immunological Memory><Immunological System Dysfunction><Immunological response><Immunologically Directed Therapy><Immunology><Immunotherapy><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammation><Institutional Review Boards><Knowledge><Learning><Link><Liver><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphatic nodes><Maps><Model System><Modern Man><Morbidity><Morbidity - disease rate><Myeloid Cells><Nature><PASC><PD 1><PD-1><PD-1 checkpoint pathway><PD-1 pathway><PD-1 signaling pathway><PD1><PD1 checkpoint pathway><PD1 pathway><PD1 signaling pathway><Pathogenesis><Pathologic><Pathway interactions><Patients><Position><Positioning Attribute><Post Acute Sequelae of COVID19><Post Acute Sequelae of SARS-CoV-2><Post Acute Sequelae of SARS-CoV2><Post Acute Sequelae of severe acute respiratory syndrome coronavirus 2><Post-Acute Sequelae of SARS-CoV-2 Infection><Productivity><RNA vaccine><RNA-based vaccine><Reaction><Research Resources><Research Specimen><Resolution><Resources><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><Scars><Serology><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-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 related corona virus 2><Sight><Specimen><Standardization><Study Subject><Sum><System><T8 Cells><T8 Lymphocytes><Testing><Tissues><Vaccination><Vaccines><Viral><Viral Diseases><Virus><Virus Diseases><Vision><Work><Wuhan coronavirus><aPD-1><aPD1><adverse sequelae of COVID><adverse sequelae of COVID-19><adverse sequelae of coronavirus disease><adverse sequelae of coronavirus disease 2019><anamnestic reaction><anti programmed cell death 1><anti programmed cell death protein 1 checkpoint pathway><anti programmed cell death protein 1 pathway><anti programmed cell death protein 1 signaling pathway><anti-PD-1><anti-PD1><anti-programmed cell death protein 1><anti-viral immunity><antiPD-1><antiPD1><antiviral immunity><cell type><chronic COVID-19 sequelae><chronic HCV infection><chronic disorder><chronic hepatitis C virus infection><chronic infection><cohort><coronavirus disease 2019><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 virus><coronavirus infectious disease-19><database management><database systems><developmental><driving><experiment><experimental research><experimental study><experiments><fitness><hCoV19><hep C><hepatic body system><hepatic organ system><hepatitis non A non B><high dimensionality><host response><human model><immune activation><immune health><immune system health><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunogen><immunoreaction><immunoresponse><infection by hepatitis c virus><insight><latency/reactivation><latent virus activation><long haul sequelae of COVID-19><long haul sequelae of coronavirus disease 2019><long-term sequelae of COVID-19><long-term sequelae of SARS-CoV-2><long-term sequelae of coronavirus disease 2019><long-term sequelae of severe acute respiratory syndrome coronavirus 2><lymph gland><lymph nodes><lymphnodes><mRNA vaccine><mRNA-based vaccine><model of human><mortality><nCoV2><non A, non B hepatitis><non-A, non-B hepatitis><pathway><persistent infection><post COVID-19 sequelae><post acute sequelae following COVID-19><post-acute sequelae following SARS-CoV-2 infection><post-acute sequelae of COVID-19><post-acute sequelae of acute COVID infection><post-acute sequelae of coronavirus disease 2019><programmed cell death 1><programmed cell death protein 1><programmed death 1><programs><reactivation from latency><relational database management systems><resolutions><response><sample collection><secondary immune response><sle2><specimen collection><systemic lupus erythematosus susceptibility 2><vaccine response><vaccine responsiveness><vaccine-induced response><viral infection><virus infection><virus-induced disease><visual function><αPD-1><αPD1>