Cytolysin-mediated neutrophil activation in streptococcal infections – mode of action and consequences for the human host

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Neutrophils are the major leukocyte component of the blood and the first recruited responders at the site of bacterial infection. Three distinct mechanisms to fight an infection are described: phagocytosis, degranulation, and formation of neutrophil extracellular traps (NETs). Critical components of all these processes are granule effector molecules, including proteolytic enzymes and antimicrobial peptides. Streptococcal species, including S. pyogenes, S. dysgalactiae subsp. equisimilis, and S. pneumoniae have evolved a distinct repertoire of protein cytotoxins that interfere with crucial neutrophil functions. One of them is their cytolytic property. Their interactions with cholesterol-rich membranes result in oligomerization, pore formation, and subsequent tissue pathology mediated by neutrophil components. However, our data and data from other laboratories suggest that these toxins can also activate neutrophils at sub-lytic concentrations without lysis. In this proposal, we are aiming to analyze neutrophil activating properties of streptolysin O and pneumolysin, Specifically, we aim to: (i) define the minimum amount of the respective toxin which is necessary for neutrophil activation, (ii) identify potential human neutrophil receptors which are targeted by the toxins, (iii) characterize the interaction and the resulting consequences, and (iv) identify natural and therapeutic neutralizing agents to be able to prevent excessive neutrophil activation and subsequent tissue pathology. We will perform comprehensive microbiological, immunological, and biochemical analyses of infected and/or stimulated human primary neutrophils. Furthermore, we will verify the obtained results in patient´s material.