Dissecting the role of cholesterol trafficking in pathogen-containing vacuole stability

• Applicant: Dr. Joel Selkrig
• Subject Area: Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 521229301

Intracellular pathogens have evolved elaborate mechanisms to protect themselves from host cell machineries, whose role is to otherwise promote their elimination. For instance, Salmonella enterica subtype Typhimurium (STm) injects a cocktail of so-called “effector” proteins into the host cytoplasm which enable the construction of a membranous shield, referred to as the Salmonella containing vacuole (SCV), and thereby preventing STm recognition by host innate immune receptors. The host factors responsible for regulating SCV integrity have so far remained elusive. We recently published that the human Niemann-Pick disease Type C1 protein (NPC1) interacts with the secreted STm effector protein SseJ. In this proposal, we provide preliminary evidence that NPC1 plays a crucial role in host cell defense by promoting SCV destabilization, thereby potentiating pathogen detection and host pyroptotic cell death. Firstly, we will explore NPC1’s well-established role in cholesterol efflux from endo-lysosomal compartments on SCV integrity. Secondly, we will further dissect the molecular mechanism(s) by which the effector SseJ, and other related effectors (e.g. SseL), counteract NPC1’s antimicrobial function. Lastly, we will examine how STm-dependent cholesterol trafficking events inside an infected host cell affect secretion of the pro-inflammatory cytokine Cxcl10. Overall, this proposal will shed light on the host factors regulating the integrity of pathogen-containing vacuolar compartments, the role of NPC1 and cholesterol in this process, and the countermeasures STm has evolved to promote its survival within the intracellular niche.

• DFG Programme: Research Grants
• International Connection: France, United Kingdom
• Cooperation Partners: Professorin Dr. Pascale Cossart; Professorin Dr. Frances Platt