Biological role of SARS-CoV2 Superantigenic structure in hyperinflammatory syndromes

项目摘要

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.