Liu Sheng, Xie Yan, Luo Wei, Dou Yafeng, Xiong Huan, Xiao Zhen, Zhang Xiao-Lian
Hubei Province Key Laboratory of Allergy and Immunology, Department of Immunology, Wuhan University School of Basic Medical Sciences and Department of Allergy, Zhongnan Hospital, Wuhan University, Wuhan, China.
State Key Laboratory of Virology, Frontier Science Center for Immunology and Metabolism, Wuhan University School of Medicine, Wuhan, China.
Front Microbiol. 2020 May 8;11:845. doi: 10.3389/fmicb.2020.00845. eCollection 2020.
() evades the surveillance of immune responses for survival in macrophages. However, the precise mechanism and toxins/proteins encoded by 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 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 (H37RvΔ1768) showed significantly decreased colony-forming units in the lungs, spleen, and liver of the murine 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 H37RvΔRv1768. 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-κB)-tumor necrosis factor α (TNF-α) 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 Rv1768 promotes mycobacterial survival in macrophages by regulating NF-κB-TNF-α signaling and arachidonic acid metabolism via S100A9. Disturbing the interaction between Rv1768 and S100A9 may be a potential therapeutic target for tuberculosis.
（）在巨噬细胞中存活以逃避免疫反应的监视。然而，参与细菌逃逸的精确机制以及所编码的毒素/蛋白质仍然不清楚。据我们所知，强毒株H37Rv菌株中缺失区域14（RD - 14）所编码的Rv1768蛋白（也称为PE_PGRS31，属于PE_PGRS家族）的功能此前尚未见报道。在此，我们发现Rv1768显著促进细菌在巨噬细胞中的存活。与野生型（WT）H37Rv相比，Rv1768缺陷菌株（H37RvΔ1768）在小鼠感染模型的肺、脾和肝脏中的集落形成单位显著减少。WT H37Rv在WT巨噬细胞和C57BL / 6小鼠中的细菌载量显著高于S100A9缺陷细胞和小鼠中的细菌载量，但H37RvΔRv1768则无显著差异。Rv1768通过脯氨酸 - 谷氨酸结构域（PE结构域）与S100A9结合，阻断S100A9与Toll样受体4（TLR4）之间的相互作用，并抑制巨噬细胞中TLR4 - 髓样分化因子88 - 核因子 - κB（NF - κB） - 肿瘤坏死因子α（TNF - α）信号传导。有趣的是，Rv1768与S100A9的结合还通过激活5 - 脂氧合酶、增加脂毒素A4以及下调环氧化酶 - 2和前列腺素E2表达来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，Rv1768通过S100A9调节NF - κB - TNF - α信号传导和花生四烯酸代谢来促进分枝杆菌在巨噬细胞中的存活。干扰Rv1768与S100A9之间的相互作用可能是结核病的一个潜在治疗靶点。
