Department of Microbiology and Immunology, Biomedical Sciences, Liver Research Institute and Cancer Research Institute, College of Medicine, Seoul National University, Seoul, South Korea.
Front Immunol. 2019 Jan 31;10:125. doi: 10.3389/fimmu.2019.00125. eCollection 2019.
complex (MAB) is a rapidly growing mycobacterium(RGM) whose clinical significance as an emerging human pathogen has been increasing worldwide. It has two types of colony morphology, a smooth (S) type, producing high glycopeptidolipid (GPL) content, and a rough (R) type, which produces low levels of GPLs and is associated with increased virulence. However, the mechanism responsible for their difference in virulence is poorly known. By ultrastructural examination of murine macrophages infected, we found that MAB-R strains could replicate more actively in the macrophage phagosome than the S variants and that they could escape into cytosol via phagosomal rupture. The cytosolic access of MAB-R strains via phagosomal rupture led to enhanced Type I interferon (IFN) production and cell death, which resulted in their cell-to-cell spreading. This behavior can provide an additional niche for the survival of MAB-R strains. In addition, we found that their enhancement of cell death mediated cell spreading are dependent on Type I IFN signaling via comparison of wild-type and IFNAR1 knockout mice. In conclusion, our data indicated that a transition of MAB-S strains into MAB-R variants increased their virulence via enhanced Type I IFN production, which led to enhanced survival in infected macrophage via cell death mediated cell-to-cell spreading. This result provides not only a novel insight into the difference in virulence between MAB-R and -S variants but also hints to their treatment strategy.
分枝杆菌复合群（MAB）是一种快速生长的分枝杆菌（RGM），其作为新兴人类病原体的临床意义在全球范围内不断增加。它有两种菌落形态，一种是光滑（S）型，产生高糖肽脂（GPL）含量，另一种是粗糙（R）型，产生低水平的 GPLs 并与增加的毒力相关。然而，导致它们毒力差异的机制知之甚少。通过对感染的鼠巨噬细胞进行超微结构检查，我们发现 MAB-R 株在巨噬细胞吞噬体中比 S 变体更能积极复制，并且它们可以通过吞噬体破裂进入细胞质。MAB-R 株通过吞噬体破裂进入细胞质导致 I 型干扰素（IFN）产生和细胞死亡增加，从而导致细胞间扩散。这种行为可以为 MAB-R 株的生存提供额外的小生境。此外，我们发现通过比较野生型和 IFNAR1 敲除小鼠，它们增强细胞死亡介导的细胞扩散依赖于 I 型 IFN 信号。总之，我们的数据表明，MAB-S 株向 MAB-R 变体的转变通过增强 I 型 IFN 产生增加了其毒力，从而通过细胞死亡介导的细胞间扩散增加了感染巨噬细胞中的存活。这一结果不仅为 MAB-R 和 -S 变体毒力差异提供了新的见解，也为其治疗策略提供了线索。
