Mycobacterium 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 clinical Mtb strains from multiple Mtb lineages, Mtb complex (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 from Mtb lineages 1, 2, 3 and 4, Mycobacterium bovis and the NTM, Mycobacterium abscessus and Mycobacterium avium. However, lipid extract from Mycobacterium 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 from Mycobacterium canettii-related mycobacteria and that this activity contributes significantly to the promotion of disease.

结核分枝杆菌( Mtb ) 在宿主巨噬细胞 (MΦ) 内存活和复制，并破坏多种抗菌防御机制。此前，我们报道了致病性分枝杆菌脱落的脂质会抑制 NPC1，NPC1 是溶酶体贮积症 C 型尼曼-皮克病 (NPC) 中缺乏的溶酶体膜蛋白。抑制 NPC1 会导致溶酶体钙水平下降，阻止吞噬体-溶酶体融合，从而导致分枝杆菌存活。我们推测抑制 NPC1 的特定细胞壁脂质的产生可能是致病性进化的关键一步。因此，我们研究了来自多个Mtb谱系的临床Mtb菌株、 Mtb复合体 (MTBC) 成员和非结核分枝杆菌 (NTM) 的脂质提取物是否抑制 NPC 途径。我们报告称，NPC 途径的抑制存在于Mtb谱系 1、2、3 和 4、牛分枝杆菌和 NTM、脓肿分枝杆菌和鸟分枝杆菌的所有临床分离株中。然而，来自卡内蒂分枝杆菌的脂质提取物（被认为类似于 MTBC 的共同祖先）并没有抑制 NPC1 途径。我们得出的结论是，NPC1 抑制性分枝杆菌细胞壁脂质的进化是从卡内蒂分枝杆菌相关分枝杆菌早期和分化后进化出来的，并且这种活性对疾病的促进有显着贡献。