Primary and secondary membrane damage by small β-barrel pore forming toxins and their implications for membrane repair
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Abstract
Bacterial Pore-forming toxins (PFTs) disturb cellular homeostasis by permeabilizing the plasma membranes of target cells. However, target cells may repair those lesions. Counterintuitively, membrane repair is comparably fast and efficient for large pores, e.g. formed by cholesterol dependent cytolysins (CDC) like streptolysin O (ca. 30 nm inner diameter), whereas it is slow for smaller pores, like those formed by S. aureus α-toxin (ca. 1.2 nm). The reasons are unclear. The first part of this thesis describes the comparison of a new small β-PFT, namely Phobalysin P (PhlyP) of Photobacterium damselae subsp. damselae with orthologous Vibrio cholerae cytolysin. The data support the conclusion that not the affiliation of a PFT with a certain structural family, but sufficient flux of calcium ions through pores determines the capacity to trigger rapid repair. The second part of the work deals with the question how secondary effects might account for concentration dependent, apparent increases of pore size in the case of S. aureus alpha-toxin. Not activation of gasdermin D (GSDMD), or Mixed lineage kinase domain like pseudokinase (MLKL), which were recently found to form large pores from the cytosolic side, seem not to be involved, but swelling-induced rupture.