Chatrath Shweta, Gupta Vineet Kumar, Dixit Aparna, Garg Lalit C
Gene Regulation Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India.
Gene Regulation Laboratory, School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India.
Microbes Infect. 2016 Sep;18(9):536-42. doi: 10.1016/j.micinf.2016.04.004. Epub 2016 Apr 27.
The success of Mycobacterium tuberculosis as a pathogen relies on its ability to survive inside macrophages and evade host immune mechanisms. M. tuberculosis employs multiple strategies to confer resistance against immune system including inhibition of phago-lysosomal fusion, modulation of cytokine responses and granuloma formation. PE_PGRS proteins, uniquely present in pathogenic mycobacteria, are cell surface molecules that are suggested to interact with host cells. PE_PGRS proteins have also been implicated in its pathogenesis. In the present study, immuno-regulatory property of Rv1651c-encoded PE_PGRS30 protein was explored. Infection of PMA-differentiated human THP-1 macrophages with Mycobacterium smegmatis harbouring pVV(1651c) resulted in reduced production of IL-12, TNF-α and IL-6, as compared to infection with M. smegmatis harbouring the control plasmid pVV16. No differential effect was observed on bacterial persistence inside macrophages or on macrophage mortality upon infection with the two recombinant strains. Infection of THP-1 macrophages with recombinant M. smegmatis expressing deletion variants of PE_PGRS30 indicated that anti-inflammatory function of the protein is possessed by its PGRS and PE domains while the C-terminal domain, when expressed alone, displayed antagonistic effect in terms of TNF-α secretion. These results suggest that PE_PGRS30 interferes with macrophage immune functions important for activation of adaptive T-cell responses.
结核分枝杆菌作为病原体的成功依赖于其在巨噬细胞内生存并逃避宿主免疫机制的能力。结核分枝杆菌采用多种策略来获得对免疫系统的抗性，包括抑制吞噬溶酶体融合、调节细胞因子反应和形成肉芽肿。PE_PGRS蛋白独特地存在于致病性分枝杆菌中，是被认为与宿主细胞相互作用的细胞表面分子。PE_PGRS蛋白也与其发病机制有关。在本研究中，探索了Rv1651c编码的PE_PGRS30蛋白的免疫调节特性。与携带对照质粒pVV16的耻垢分枝杆菌感染相比，用携带pVV(1651c)的耻垢分枝杆菌感染经佛波酯分化的人THP-1巨噬细胞，导致IL-12、TNF-α和IL-6的产生减少。在用这两种重组菌株感染后，未观察到对巨噬细胞内细菌存活或巨噬细胞死亡率的差异影响。用表达PE_PGRS30缺失变体的重组耻垢分枝杆菌感染THP-1巨噬细胞表明，该蛋白的抗炎功能由其PGRS和PE结构域所具有，而单独表达的C末端结构域在TNF-α分泌方面表现出拮抗作用。这些结果表明，PE_PGRS30干扰了对适应性T细胞反应激活很重要的巨噬细胞免疫功能。
