结核分枝杆菌PE5通过先天免疫toll样受体4信号传导刺激抗炎细胞因子的产生。

IF 3.5 3区 医学 Q3 IMMUNOLOGY
Microbial pathogenesis Pub Date : 2025-11-01 Epub Date: 2025-08-06 DOI:10.1016/j.micpath.2025.107966
Farha Naz, Mohd Arish, Sugandha Singh, Nilofer Naqvi, Anwar Alam
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引用次数: 0

摘要

结核分枝杆菌拥有一个复杂的毒力因子系统,有助于在宿主环境中提供对病原体的恢复力。结核分枝杆菌表达独特的蛋白PE/PPE,这些蛋白是保守的,在发病机制中起关键作用。结核分枝杆菌(M.tb) PE家族的一个保守成员Rv0285 (PE5)早先被定性为宿主免疫反应的关键调节因子的必需和分泌蛋白。我们已经证明PE5蛋白由溶酶体靶向序列组成,并且在低pH下稳定,从而允许蛋白质定位到溶酶体上。芯片研究表明PE5与TLR4相互作用。使用TLRs敲除巨噬细胞系验证了这一点。PE5通过TLR4受体增加抗炎细胞因子。与对照的耻垢分枝杆菌相比,表达M.tb-PE5蛋白的重组耻垢分枝杆菌在巨噬细胞内存活,表明其在巨噬细胞内提供生存弹性方面的作用。FDA对与PE5蛋白相互作用的药物进行了筛选。制霉菌素和盐酸康尼伐坦与PE5的相互作用导致稳定的结合,并为这些分子作为抗结核药物的可能性提供了概念证明。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Mycobacterium tuberculosis PE5 stimulates anti-inflammatory cytokine production via innate immune toll-like receptor 4 signaling.

Mycobacterium tuberculosis possesses an intricate system of virulence factors that aid in providing resilience to the pathogen within the milieu of the host. M.tb expresses unique proteins, PE/PPE, that are conserved and play a crucial role in pathogenesis. A conserved member of the PE family Rv0285 (PE5) of Mycobacterium tuberculosis (M.tb) has been earlier characterized as an essential and secretory protein that is a critical regulator of host immune response. We have shown that the PE5 protein consists of lysosomal targeting sequences and is stable at low pH, thereby allowing the protein to be localized to the lysosome. In-silico studies suggest that PE5 interacts with TLR4. This was validated using the TLRs knockout macrophage cell lines. PE5 increases the anti-inflammatory cytokine via the TLR4 receptor. Recombinant M. smegmatis expressing M.tb-PE5 protein survives within the macrophage as compared to control M. smegmatis, suggesting its role in providing resilience to survive within the macrophage. FDA drugs were screened for that interaction with the PE5 protein. Interaction of Nystatin and Conivaptan hydrochloride with PE5 results in stable binding and provides proof of concept about the possibility of repurposing these molecules as an anti-tubercular drug.

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来源期刊
Microbial pathogenesis
Microbial pathogenesis 医学-免疫学
CiteScore
7.40
自引率
2.60%
发文量
472
审稿时长
56 days
期刊介绍: Microbial Pathogenesis publishes original contributions and reviews about the molecular and cellular mechanisms of infectious diseases. It covers microbiology, host-pathogen interaction and immunology related to infectious agents, including bacteria, fungi, viruses and protozoa. It also accepts papers in the field of clinical microbiology, with the exception of case reports. Research Areas Include: -Pathogenesis -Virulence factors -Host susceptibility or resistance -Immune mechanisms -Identification, cloning and sequencing of relevant genes -Genetic studies -Viruses, prokaryotic organisms and protozoa -Microbiota -Systems biology related to infectious diseases -Targets for vaccine design (pre-clinical studies)
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