SIGNALIS · Mimicry of host cell functions by microbial pathogens: subversion of ceramide signalling by a bacterial (Listeria) sphingomyelinase during intracellular infection

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Project objective

Degradation of sphingomyelin (SM) by a sphingomyelinase (SMase) generates ceramide, a lipid metabolite increasingly recognised as an important pro-apoptotic mediator. The exact role of ceramide in apoptosis is unclear and aspects such as the source SM pool, and whether a membrane-associated neutral SMase (nSMase) or a lysosomal acid SMase is primarily involved, remain also to be defined. In this project, we will exploit the Listeria model of intracellular parasitism and an nSMase produced by these pathogenic bacteria, SmcL, identified and characterised in the host laboratory, to gain a better understanding of the role played by ceramide in host cell physiology, with particular emphasis on the apoptotic response. SmcL also provides a beautiful model to analyse how mimicry of host cell physiological functions by bacterial virulence factors contributes to the pathogenesis of infection.The host cell responses associated to SmcL-generated ceramide will be analysed during intracellular infection by using genome-wide transcriptome profiling and the specific pathways affected will be dissected by using a combination of molecular and cell biology techniques. Finally, we will also attempt to crystallise SmcL in collaboration with structural biologists. If successful, S mcL will become the first example of the neutral SMase family, a new group of SM-degrading enzymes comprising bacterial and eukaryotic orthologues with roles in virulence and signalling, to be characterised structurally.

Original text from CORDIS.

Participants

• UNIVERSITY OF BRISTOL · BRISTOL, CLIFTONCoordinatorUnited Kingdom

Links

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