Dangerous Proteins and Where to Find Them- Structural and functional studies of bacterial and viral proteins interacting with human immune receptors in health and disease

Abstract: Bacteria and viruses are threats to human that evolved strategies to bypass the immune system and can cause massive damage. Understanding these strategies and elucidating pathogen interacting partners within the human immune system will pave the way for discovery of new medicines and increase human well-being. Superantigens (SAgs) are toxins that induce a massive immune response, causing sever diseases. The bacteria Staphylococcus aureus produces staphylococcal enterotoxins (SEs) that are the focus of this thesis. In human, SEs are presented by major histocompatibility complex II (MHCII) to T cell receptors (TCRs), located on T cells, leading to clonal expansion of respective T cells and an overactivation of the immune system. This T cell skewing, that is one of the hallmarks for superantigens, has also been seen for the corona virus. The spike protein that is on the surface of the corona virus, partly structurally resembles a superantigen and its superantigenic character must be analysed to further understand disease development.In this thesis, I will describe and discuss my structural and functional data of superantigens, and the superantigen-like spike protein interacting with human immune receptors and put them into context with the current knowledge of the immune system and try to highlight their implication in disease development in human.My work has resulted in new findings within the field of superantigen biology. Firstly, the SEs, SEA and SEH, were shown to interact with γδ T cells from human peripheral blood in an indirect mechanism utilizing monocytes and αβ T cells. Moreover, SEA was shown to bind γδ TCR (Vγ9δ2) directly in a protein interaction experiment. The biological outcome of this interaction is still unknown. Secondly, the interaction of SEA, SEE and SEH with the human cytokine receptor gp130 is further analysed. It was shown that their binding affinity differs and that they do not bind rodent gp130, suggesting a different mode of action in human. A computational model of SEA complexed with gp130 was generated. Taken together, our data supported by previous experiments indicates that the SEA-gp130 interaction might have implications in emesis. Finally, the spike glycoprotein in SARS-CoV-2 was shown to have superantigenic character, because of its sequential and structural similarity with SEB. Here, we show that specific TRBV of TCRs bind presumably the NTD/RBD domain of the spike glycoprotein.