Inhibition of the Niemann-Pick C1 protein is a conserved feature of multiple strains of pathogenic mycobacteria

Journal article

AbstractMycobacterium tuberculosis(Mtb) survives and replicates within host macrophages (MΦ) and subverts multiple antimicrobial defense mechanisms. Previously, we reported that lipids shed by pathogenic mycobacteria inhibit NPC1, the lysosomal membrane protein deficient in the lysosomal storage disorder Niemann-Pick disease type C (NPC). Inhibition of NPC1 leads to a drop in lysosomal calcium levels, blocking phagosome-lysosome fusion leading to mycobacterial survival. We speculated that the production of specific cell wall lipid(s) that inhibit NPC1 could have been a critical step in the evolution of pathogenicity. We therefore investigated whether lipid extracts from clinicalMtbstrains from multipleMtblineages,Mtbcomplex (MTBC) members and non-tubercular mycobacteria (NTM) inhibit the NPC pathway. We report that inhibition of the NPC pathway was present in all clinical isolates fromMtblineages 1, 2, 3 and 4,Mycobacterium bovisand the NTM,Mycobacterium abscessusandMycobacterium avium. However, lipid extract fromMycobacterium canettii, which is considered to resemble the common ancestor of the MTBC did not inhibit the NPC1 pathway. We conclude that the evolution of NPC1 inhibitory mycobacterial cell wall lipids evolved early and post divergence fromMycobacterium canettii-related mycobacteria and that this activity contributes significantly to the promotion of disease.

Authors: Weng, Y; Shepherd, D; Liu, Y; Krishnan, N; Robertson, BD

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature Communications
• Volume: 13
• Issue: 1
• Pages: 5320-5320
• Article number: 5320
• Publication date: 2022-09-09
• DOI: 10.1038/s41467-022-32553-0
• EISSN: 2041-1723
• ISSN: 2041-1723
• Language: English
• Keywords: Mycobacterium abscessus; Biology; Immunology; Microbiology; Bacteria; Cell; Mycobacterium bovis; Genetics; Tuberculosis; NPC1; Medicine; Mycobacterium marinum; Virology; Mycobacterium tuberculosis; Mycobacterium; Mycobacterium leprae