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Principal Investigator: Moshe Arditi
Organization: CEDARS-SINAI MEDICAL CENTER
Fiscal Year: 2020
Award: $184,894
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT ABSTRACT
The Coronavirus Disease 2019 (COVID-19) pandemic has been associated with the emergence of a new febrile
pediatric entity called multisystem inflammatory syndrome in children (MIS-C), that involved systemic
hyperinflammation, multiorgan involvement and gastrointestinal symptoms. In some cases, this syndrome also
demonstrated clinical attributes, such as persistent fever, rashes, conjunctivitis and generalized pain in the
extremities, that mirror some features observed during Kawasaki Disease (KD). MIS-C patients are critically ill
and present with prominent cardiogenic shock and impressive myocardial dysfunction. While initially designated
as “Kawasaki-like” because of the few features that were reminiscent of KD, it has been suggested that the
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can trigger KD in children, however many
clinical laboratory as well as cardiac findings indicate that MIS-C and KD are different entities, and that MIS-C
presents more similarities with toxic shock syndrome (TSS), which is triggered by bacterial or viral superantigens.
In recognition of the NIH Strategic Plan and the urgent need for research on Coronavirus Disease 2019 (COVID-
19) and its causative agent, SARS-CoV-2, here we propose to expand the planned studies of our R01 by adding
experiments examining the role of SARS-CoV-2 superantigenic activity and its connection to the emergence of
MIS-C. Our preliminary computational analysis of SARS-CoV-2 suggest that the virus has a superantigen (SAg)
motif between the S1 and S2 spike proteins. However, this specific finding needs to be assessed biologically in
MIS-C patients and by in vitro experiments using human PBMCs.
Therefore, we hypothesize that KD and MIS-C are distinct entities triggered by different immune mechanisms,
and that the aberrant immune response observed in MIS-C patients is the result of SARS-CoV-2 superantigenic
stimulation. We propose to investigate the hypothesis that the SARS-CoV-2 SAg motif triggers
hyperinflammation in MIS-C patients and severe COVID-19 cases by performing the following supplemental
specific AIMS 1) Determine the involvement of a Superantigen (SAg) in the pathogenesis of Multisystem
Inflammatory Syndrome in Children (MIS-C) by characterization of the MIS-C patient T Cell Receptor
(TCR) repertoire and 2) Determine if the Spike protein of SARS-CoV-2 possesses superantigen-like
activity in vitro and in vivo. Successful completion of the aims of this administrative supplement could reveal
new avenues to predict, prevent, and treat MIS-C and severe COVID-19 disease in adults.
Terms: <0-11 years old><2019 novel coronavirus><2019-nCoV><21+ years old><Acute><Administrative Supplement><Adult><Adult Human><Aneurysm><Angiitis><Antigens><Aortic Aneurysm><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Biological><Biology><Blood Vessels><COVID-19><COVID-19 epidemic><COVID-19 pandemic><COVID19><COVID19 epidemic><COVID19 pandemic><Cardiac><Cardiac Diseases><Cardiac Disorders><Cardiac artery><Cardiogenic Shock><Cardiovascular Diseases><Causality><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Characteristics><Child><Child Youth><Childhood><Children (0-21)><Clinical><Communities><Computer Analysis><Conjunctivitis><Coronary artery><Critical Illness><Critically Ill><Development><Disease><Disorder><Elements><Etiology><Exanthem><Exanthema><Extremities><Fever><Grant><Heart Diseases><Heart artery><Human><IL-1><IL1><Immune><Immune response><Immunes><Immunological response><In Vitro><Infection><Inflammation><Inflammatory><Interleukin I><Interleukin-1><Intracellular Communication and Signaling><Kawasaki Disease><Laboratories><Ligands><Limb structure><Limbs><Lymphocyte-Stimulating Hormone><MHC Receptor><MMP-3><Macrophage Cell Factor><Major Histocompatibility Complex Receptor><Matrix Metalloproteinase 3><Mediating><Modern Man><Mucocutaneous Lymph Node Syndrome><Myocardial depression><Myocardial dysfunction><Myocarditis><Myofibroblast><NIH><National Institutes of Health><Non-Trunk><PBMC><Pain><Painful><Parents><Pathogenesis><Pathology><Peptide antibodies><Peripheral Blood Mononuclear Cell><Play><Prevention><Proteins><Pyrexia><Rash><Receptors, Antigen, T-Cell><Reporting><Research><Role><SARS-CoV-2><SARS-CoV2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><Severe acute respiratory syndrome coronavirus 2><Signal Transduction><Signal Transduction Systems><Signaling><Skin Rash><Specificity><Strategic Planning><Stromelysin><Stromelysin 1><Structure><Superantigens><Syndrome><T Helper Factor><T-Cell Receptor><T-Cells><T-Lymphocyte><T-cell receptor repertoire><TCR repertoire><Toxic Shock><Toxic Shock Syndrome><Transin-1><United States National Institutes of Health><Vascular Diseases><Vascular Disorder><Vasculitis><Viral><Virus><Wuhan coronavirus><abdominal aorta><adulthood><aorta aneurysm><biological signal transduction><blood vessel disorder><cardiac dysfunction><cardiac inflammation><cardiovascular disorder><causation><child patients><children><childrens'><collagenase activating protein><computational analyses><computational analysis><computer analyses><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease 2019><coronavirus disease 2019 epidemic><coronavirus disease 2019 pandemic><developmental><disease causation><experiment><experimental research><experimental study><febrile><febris><gastrointestinal symptom><heart disorder><heart dysfunction><host response><immunogen><immunoresponse><in vitro activity><in vivo><lymphocyte activating factor><novel><pediatric><pediatric patients><peptide mimetic><peptide mimic><peptidomimetics><prevent><preventing><procollagenase activator><proteoglycanase><social role><thymus derived lymphocyte><vascular><vascular dysfunction><vasculitides><vasculopathy><youngster>