Dottorato in BIOLOGIA CELLULARE E DELLO SVILUPPO

Titolo della tesi: Characterization of the mechanisms and signalling mediators regulating human toxic shock in response to bacterial superantigens

Staphylococcus aureus is gram-positive bacterium that produces enterotoxins that act as superantigens (SAgs), such as staphylococcal enterotoxin A (SEA) and B (SEB). SAgs are potent toxins that activate T cells to elicit an excessive and harmful inflammatory response known as toxic shock syndrome (TSS). The inflammatory activity of staphylococcal SAgs relies on their ability to bind the T-cell receptor (TCR) and the costimulatory receptor CD28 on T cells as well as the major histocompatibility class II (MHC-II) and B7 molecules on antigen presenting cells (APC). Starting from these evidences, this thesis was aimed to better characterize the role of these molecules on SAg-mediated inflammatory responses. Our data demonstrate that the binding of SEB and SEA to either MHC-II or B7 molecules is dispensable for the activation of inflammatory signals, whereas the binding to the TCR and CD28 is pivotal. Interestingly, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the coronavirus disease 2019 (COVID-19), several weeks after infection, promotes in some children a rare hyperinflammatory disease named multisystem inflammatory syndrome in children (MIS-C) that shares clinical similarity with TSS induced by SAgs. Moreover, recent in silico models suggested the presence in SARS-CoV-2 spike protein of a conserved motif similar in structure to a fragment SEB. However, no experimental data on the superantigenic activity of SARS-CoV-2 spike are avilable. Hence, we also assessed the superatigenic activity of SARS-CoV-2 spike. Our data demonstrate that SARS-CoV-2 spike does not possess an intrinsic superantigenic-like activity. Finally, we highlighted a novel model of T cell activation by staphylococcal SAgs, which by binding the TCR and CD28 in a bivalent way promote a toxic inflammatory response in the absence of APCs.