PE_PGRS31-S100A9 Interaction Promotes Mycobacterial Survival in Macrophages Through the Regulation of NF-κB-TNF-α Signaling and Arachidonic Acid Metabolism
PE_PGRS31-S100A9 Interaction Promotes Mycobacterial Survival in Macrophages Through the Regulation of NF-κB-TNF-α Signaling and Arachidonic Acid Metabolism
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DOI：
10.3389/fmicb.2020.00845
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发表时间：
2020-05-08
影响因子：
5.2
通讯作者：
Zhang, Xiao-Lian
中科院分区：
文献类型：
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作者：
Liu, Sheng;Xie, Yan;Zhang, Xiao-Lian
结核分枝杆菌(M.TB)逃避巨噬细胞生存的免疫反应的监测。然而，结核分枝杆菌参与细菌逃逸的确切机制和编码的毒素/蛋白质仍然不清楚。在结核分枝杆菌H37Rv强毒株中，Rv1768蛋白(又称PE_PGRS31，属于PE_PGRs家族)缺失14区(RD-14)编码的功能尚未见报道。在这里，我们发现Rv1768显著促进了细菌在巨噬细胞中的存活。与野生型(WT)H37Rv相比，Rv1768缺陷株(H37Rv Delta 1768)在小鼠结核分枝杆菌感染模型的肺、脾和肝脏中的克隆形成单位显著减少。WT H37Rv在WT巨噬细胞和C57BL/6小鼠体内的细菌载量显著高于S100A9缺陷细胞和小鼠，而H37Rv Delta Rv1768的细菌载量无显著差异。Rv1768结合S100A9的PE结构域，阻断S100A9与Toll样受体4(TLR4)的相互作用，抑制TLR4-髓系分化因子88-核因子-kappaB(NF-kappa B)-肿瘤坏死因子-α(TNF-α)信号转导。有趣的是，与S100A9结合的Rv1768还通过激活5-脂氧合酶，增加脂毒素A4，下调环氧合酶-2和前列腺素E2的表达，干扰花生四烯酸的代谢，从而促进分枝杆菌的存活。我们的结果表明，结核分枝杆菌Rv1768通过S100A9调节核因子-kappa B-肿瘤坏死因子-α信号和花生四烯酸代谢，从而促进分枝杆菌在巨噬细胞中的存活。干扰Rv1768和S100A9之间的相互作用可能是治疗结核病的潜在靶点。
Mycobacterium tuberculosis (M. tb) evades the surveillance of immune responses for survival in macrophages. However, the precise mechanism and toxins/proteins encoded by M. tb involved in the bacterial escape remain elusive. The function of Rv1768 protein (also referred to as PE_PGRS31, belonging to the PE_PGRS family) encoded by the region of deletion 14 (RD-14) in the virulent M. tb H37Rv strain has not, to the best of our knowledge, been reported previously. Here, we found that Rv1768 remarkably promotes bacterial survival in macrophages. Compared to wild type (WT) H37Rv, the Rv1768 deficient strain (H37Rv Delta 1768) showed significantly decreased colony-forming units in the lungs, spleen, and liver of the murine M. tb infection model. The bacterial burdens of WT H37Rv in WT macrophages and C57BL/6 mice were significantly higher than those in S100A9 deficiency cells and mice, but there were no significant differences for H37Rv Delta Rv1768. Rv1768 binds S100A9 with the proline-glutamic acid domain (PE domain) and blocks the interaction between S100A9 and Toll-like receptor 4 (TLR4), and suppresses TLR4-myeloid differentiation factor 88-nuclear factor-kappa B (NF-kappa B)-tumor necrosis factor alpha (TNF-alpha) signaling in macrophages. Interestingly, Rv1768 binding to S100A9 also disturbs the metabolism of arachidonic acid by activating 5-lipoxygenase, increasing lipotoxin A4, and down-regulating cyclooxygenase-2 and prostaglandin E2 expression, thus, promoting mycobacterial survival. Our results revealed that M. tb Rv1768 promotes mycobacterial survival in macrophages by regulating NF-kappa B-TNF-alpha signaling and arachidonic acid metabolism via S100A9. Disturbing the interaction between Rv1768 and S100A9 may be a potential therapeutic target for tuberculosis.