Kristin Juliet Fritsch

• Earlier studies regarded mainly membrane cholesterol as the cellular receptor for cholesterol dependent cytolysins (CDCs) like pneumolysin but growing evidence suggests a crucial role for glycans as possible receptors or mediators. However, their precise role remains unclear. This doctoral thesis aimed to examine the interactions of pneumolysin from S. pneumoniae with human platelets. Especially the role of the two neuraminidases NanH from C. perfringens and NanA from S. pneumoniae in the toxin’s pathogenesis was investigated. Moreover, the inhibitory effects of intravenous immunoglobulin (IVIG) and the neuraminidase inhibitor Oseltamivir Carboxylate (OC) on NanA were studied. My findings demonstrated that treatment with NanA (S. pneumoniae) or NanH (C. perfringens) leads to desialylation of platelet glycoproteins. This concentration dependent increase in desialylation enhances the binding of pneumolysin to platelets as well as the toxin’s effects – namely pore formation and lysis. NanA and NanH also enhance the binding of pneumolysin in low concentrations, while NanA is further able to enhance the destructive effects of such low concentrations. On the one hand, IVIG is able to inhibit NanA dependent desialylation of platelet glycoproteins and hence, the toxin’s pore forming effects. On the other hand, OC is able to partially inhibit NanA. Desialylation of platelet glycoproteins is inhibited by OC but apparently not sufficiently. As a result, the destructive effects of pneumolysin are unhindered. Very little information is known about the cellular receptor for pneumolysin. My findings thus shed a light on this topic, but further in vivo research with different S. pneumoniae strains is necessary. Moreover, the role of other exoglycosidases like β-galactosidase A in the pathogenesis of pneumolysin should be investigated in the future.