The NPC pathway and persistence of intracellular pathogens

Thesis

Intracellular pathogens have the ability to survive and replicate within host cells, resulting in their long-term cellular and systemic persistence. A pivotal strategy for achieving this persistence is through the prevention of phagosome-lysosome fusion. Studies by Fineran et al. have established a mechanistic link between Mycobacterium tuberculosis (Mtb) infection and Niemann-Pick disease type C (NPC), a rare lysosomal storage disorder. Mtb infection involves the shedding of microbial lipids that inhibit NPC1 in host cells. Our study has confirmed that the lipid-mediated inhibition of NPC1 is widespread in clinically relevant global human Mtb strains. However, we observed no such inhibition with lipid extracts from Mycobacterium canettii, an ancestral species of modern human Mtb strains. These findings imply that the evolution of NPC1 inhibition conferred greater virulence of Mtb strains. Analysis of sphingolipids revealed that Mtb H37Rv lipid extract manipulates sphingosine metabolism. By analysing the activity of fractionated Mtb H37Rv lipid and commercially obtained purified Mtb lipid components, we have identified several candidates, including SL-1 and PIMs, that may be involved in the inhibition of the NPC pathway. In addition, we have identified Salmonella enterica serovar Typhimurium (S. Typhimurium), another intracellular pathogen, which inhibits the host cell NPC pathway and induces NPC cellular phenotypes. We have found that NPC1 inhibition is independent of the effector protein secreted during infection, and that lipid extract from S. Typhimurium can induce comparable NPC cellular phenotypes to live infection models. Our study therefore shows for the first time the involvement of the NPC pathway in the persistence of multiple intracellular pathogens.

Authors: Weng, Y

• DOI: 10.5287/ora-v0v7dnark
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: lipid; lysosomal storage disease; Niemann-Pick; intracellular pathogens; Mycobacterium tuberculosis; Salmonella; lysosome
• Subjects: Niemann-Pick diseases; Lipids; Mycobacteria; Lysosomes; Salmonella; Pathogenic microorganisms