Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Infect Immun. 2011 Aug;79(8):3053-63. doi: 10.1128/IAI.01108-10. Epub 2011 May 16.
Mycobacterium tuberculosis is an intracellular bacterium that persists in phagosomes of myeloid cells. M. tuberculosis-encoded factors support pathogen survival and reduce fusion of phagosomes with bactericidal lysosomal compartments. It is, however, not entirely understood if host factors that mediate endosomal fusion affect M. tuberculosis intracellular localization and survival. Neither is it known if endosomal fusion influences induction of host immune reactivity by M. tuberculosis-infected cells. Lysosomal degradation of M. tuberculosis appears to be pivotal for making available lipid substrates for assembly into lipid-CD1d complexes to allow activation of CD1d-restricted invariant natural killer T (iNKT) cells. To clarify the role for endosomal fusion in M. tuberculosis survival and induction of host CD1d-mediated immune defense, we focused our studies on the invariant chain (Ii). Ii regulates endosome docking and fusion and thereby controls endosomal transport. Through direct binding, Ii also directs intracellular transport of the class II major histocompatibility complex and CD1d. Our findings demonstrate that upon infection of Ii-knockout (Ii(-/-)) macrophages, M. tuberculosis is initially retained in early endosomal antigen 1-positive lysosomal-associated membrane protein 1-negative phagosomes, which results in slightly impaired pathogen replication. The absence of Ii did not affect the ability of uninfected and infected macrophages to produce nitric oxide, tumor necrosis factor alpha, or interleukin-12. However, induction of cell surface CD1d was impaired in infected Ii(-/-) macrophages, and CD1d-restricted iNKT cells were unable to suppress bacterial replication when they were cocultured with M. tuberculosis-infected Ii(-/-) macrophages. Thus, while the host factor Ii is not essential for the formation of the M. tuberculosis-containing vacuole, its presence is crucial for iNKT cell recognition of infected macrophages.
结核分枝杆菌是一种胞内菌，存在于髓样细胞的吞噬体中。结核分枝杆菌编码的因子支持病原体的存活，并减少吞噬体与杀菌溶酶体隔室的融合。然而，尚不完全清楚介导内体融合的宿主因子是否会影响结核分枝杆菌的细胞内定位和存活。也不知道内体融合是否会影响结核分枝杆菌感染细胞诱导宿主免疫反应的能力。溶酶体降解结核分枝杆菌似乎对于将脂质底物用于组装成脂质-CD1d 复合物以激活 CD1d 限制性固有自然杀伤 T(iNKT)细胞是至关重要的。为了阐明内体融合在结核分枝杆菌存活和诱导宿主 CD1d 介导的免疫防御中的作用，我们将研究重点放在不变链（Ii）上。Ii 调节内体对接和融合，从而控制内体运输。通过直接结合，Ii 还指导 II 类主要组织相容性复合物和 CD1d 的细胞内运输。我们的研究结果表明，在 Ii 敲除（Ii(-/-)）巨噬细胞感染后，结核分枝杆菌最初被保留在早期内体抗原 1 阳性溶酶体相关膜蛋白 1 阴性吞噬体中，这导致病原体复制略有受损。Ii 的缺失不影响未感染和感染的巨噬细胞产生一氧化氮、肿瘤坏死因子-α或白细胞介素-12 的能力。然而，感染的 Ii(-/-)巨噬细胞表面 CD1d 的诱导受到损害，当与感染的 Ii(-/-)巨噬细胞共培养时，CD1d 限制性 iNKT 细胞无法抑制细菌复制。因此，尽管宿主因子 Ii 对于形成含有结核分枝杆菌的空泡不是必需的，但它的存在对于 iNKT 细胞识别感染的巨噬细胞至关重要。
