Biological role of SARS-CoV2 Superantigenic structure in hyperinflammatory syndromes

PROJECT Abstract: The Coronavirus Disease 2019 (COVID-19) pandemic has been associated with the emergence of a new febrilepediatric entity called multisystem inflammatory syndrome in children (MIS-C), that involved systemichyperinflammation, multiorgan involvement and gastrointestinal symptoms. In some cases, this syndrome alsodemonstrated clinical attributes, such as persistent fever, rashes, conjunctivitis and generalized pain in theextremities, that mirror some features observed during Kawasaki Disease (KD). MIS-C patients are critically illand present with prominent cardiogenic shock and impressive myocardial dysfunction. While initially designatedas "Kawasaki-like" because of the few features that were reminiscent of KD, it has been suggested that thesevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can trigger KD in children, however manyclinical laboratory as well as cardiac findings indicate that MIS-C and KD are different entities, and that MIS-Cpresents 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 addingexperiments examining the role of SARS-CoV-2 superantigenic activity and its connection to the emergence ofMIS-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 inMIS-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 superantigenicstimulation. We propose to investigate the hypothesis that the SARS-CoV-2 SAg motif triggershyperinflammation in MIS-C patients and severe COVID-19 cases by performing the following supplementalspecific AIMS 1) Determine the involvement of a Superantigen (SAg) in the pathogenesis of MultisystemInflammatory 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-likeactivity in vitro and in vivo. Successful completion of the aims of this administrative supplement could revealnew avenues to predict, prevent, and treat MIS-C and severe COVID-19 disease in adults.