Institutes of Microbiology Physics, Universita' Cattolica del Sacro Cuore, Rome, Italy.
Cell Microbiol. 2012 Mar;14(3):356-67. doi: 10.1111/j.1462-5822.2011.01721.x. Epub 2011 Dec 13.
The role and function of PE_PGRS proteins of Mycobacterium tuberculosis (Mtb) remains elusive. In this study for the first time, Mtb isogenic mutants missing selected PE_PGRSs were used to investigate their role in the pathogenesis of tuberculosis (TB). We demonstrate that the MtbΔPE_PGRS30 mutant was impaired in its ability to colonize lung tissue and to cause tissue damage, specifically during the chronic steps of infection. Inactivation of PE_PGRS30 resulted in an attenuated phenotype in murine and human macrophages due to the inability of the Mtb mutant to inhibit phagosome-lysosome fusion. Using a series of functional deletion mutants of PE_PGRS30 to complement MtbΔPE_PGRS30, we show that the unique C-terminal domain of the protein is not required for the full virulence. Interestingly, when Mycobacterium smegmatis recombinant strain expressing PE_PGRS30 was used to infect macrophages or mice in vivo, we observed enhanced cytotoxicity and cell death, and this effect was dependent upon the PGRS domain of the protein.Taken together these results indicate that PE_PGRS30 is necessary for the full virulence of Mtb and sufficient to induce cell death in host cells by the otherwise non-pathogenic species M. smegmatis, clearly demonstrating that PE_PGRS30 is an Mtb virulence factor.
结核分枝杆菌（Mtb）的 PE_PGRS 蛋白的作用和功能仍不清楚。在这项研究中，我们首次使用缺失选定的 PE_PGRS 的 Mtb 同基因突变体来研究它们在结核病（TB）发病机制中的作用。我们证明，MtbΔPE_PGRS30 突变体在定植肺组织和引起组织损伤的能力方面受损，特别是在感染的慢性阶段。由于 Mtb 突变体无法抑制吞噬体-溶酶体融合，因此 PE_PGRS30 的失活导致鼠和人巨噬细胞中的减毒表型。使用一系列 PE_PGRS30 的功能缺失突变体来互补 MtbΔPE_PGRS30，我们表明该蛋白独特的 C 末端结构域对于完全毒力不是必需的。有趣的是，当表达 PE_PGRS30 的耻垢分枝杆菌重组菌株用于感染巨噬细胞或体内小鼠时，我们观察到增强的细胞毒性和细胞死亡，并且该效应依赖于该蛋白的 PGRS 结构域。总之，这些结果表明 PE_PGRS30 是 Mtb 完全毒力所必需的，并且足以通过原本非致病性的耻垢分枝杆菌诱导宿主细胞死亡，清楚地表明 PE_PGRS30 是 Mtb 的毒力因子。
