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- Mata Forsberg, Manuel, et al.
(author)
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Activation of human γδ T cells and NK cells by Staphylococcal enterotoxins requires both monocytes and conventional T cells
- 2022
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In: Journal of Leukocyte Biology. - 0741-5400 .- 1938-3673. ; 111:3, s. 597-609
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Journal article (peer-reviewed)abstract
- Staphylococcal enterotoxins (SE) pose a great threat to human health due to their ability to bypass antigen presentation and activate large amounts of conventional T cells resulting in a cytokine storm potentially leading to toxic shock syndrome. Unconventional T- and NK cells are also activated by SE but the mechanisms remain poorly understood. In this study, the authors aimed to explore the underlying mechanism behind SE-mediated activation of MAIT-, γδ T-, and NK cells in vitro. CBMC or PBMC were stimulated with the toxins SEA, SEH, and TSST-1, and cytokine and cytotoxic responses were analyzed with ELISA and flow cytometry. All toxins induced a broad range of cytokines, perforin and granzyme B, although SEH was not as potent as SEA and TSST-1. SE-induced IFN-γ expression in MAIT-, γδ T-, and NK cells was clearly reduced by neutralization of IL-12, while cytotoxic compounds were not affected at all. Kinetic assays showed that unconventional T cell and NK cell-responses are secondary to the response in conventional T cells. Furthermore, co-cultures of isolated cell populations revealed that the ability of SEA to activate γδ T- and NK cells was fully dependent on the presence of both monocytes and αβ T cells. Lastly, it was found that SE provoked a reduced and delayed cytokine response in infants, particularly within the unconventional T and NK cell populations. This study provides novel insights regarding the activation of unconventional T- and NK cells by SE, which contribute to understanding the vulnerability of young children towards Staphylococcus aureus infections.
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| 2. |
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| 3. |
- Uzuncayir, Sibel, et al.
(author)
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Analyses of the complex formation of staphylococcal enterotoxin A and the human gp130 cytokine receptor
- 2022
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In: FEBS Letters. - : Wiley. - 1873-3468 .- 0014-5793. ; 596:7, s. 910-923
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Journal article (peer-reviewed)abstract
- Superantigens (SAgs) are bacterial enterotoxins produced by Staphylococcus aureus. Staphylococcal enterotoxin type A (SEA), a staphylococcal superantigen, has been shown to bind to the cytokine signalling receptor glycoprotein 130 (gp130). The structural details, as well as the exact physiological role of this interaction, remain unclear. Here, we describe the structural details of the SEA–gp130 complex by combining crosslinking mass spectrometry and computational modelling. Interestingly, SEA is not able to bind gp130-homologues from rat and mouse. Our data suggest that SEA may interact with human gp130 in a different manner than other known gp130-ligands. Moreover, the fact that SEA does not bind mouse or rat gp130 suggests that SAgs have additional mechanisms of action in humans.
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| 4. |
- Uzuncayir, Sibel
(author)
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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
- 2022
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Doctoral thesis (other academic/artistic)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.
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