Distinct Role of TNFR1 and TNFR2 in Protective Immunity Against Orientia tsutsugamushi Infection in Mice.
Distinct Role of TNFR1 and TNFR2 in Protective Immunity Against Orientia tsutsugamushi Infection in Mice.
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DOI：
10.3389/fimmu.2022.867924
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发表时间：
2022
影响因子：
7.3
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中科院分区：
文献类型：
--
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恙虫病东方体是一种专性细胞内细菌，感染后可引起轻度或重度恙虫病。一些患者发生急性肺损伤、多器官衰竭和致命性感染;然而，关于介导感染控制或疾病发病机制的关键免疫介质知之甚少。利用恙虫病小鼠模型，我们在这项研究中证明了TNF-TNFR信号在保护性免疫中对这种感染的要求。同时缺乏TNF受体（TNFR 1和TNFR 2）的小鼠对O.恙虫病感染，显示显著增加的组织细菌负荷并在第9天死于感染，而大多数野生型小鼠存活至第20天。这种增加的易感性与发炎组织中细胞免疫的不良活化相关。肺和脾来源的细胞的流式细胞术显示NK细胞、中性粒细胞和巨噬细胞以及CD 4和CD 8 T细胞的总数和活化状态严重不足。为了明确单个受体在O.在恙虫病感染后，我们使用缺乏TNFR 1或TNFR 2的小鼠。虽然任一受体单独缺乏就足以增加宿主对感染的易感性，但TNFR 1和TNFR 2在细胞反应中起着不同的作用。通过TNFR 1的TNF信号传导促进炎症反应和效应T细胞扩增，而TNFR 2信号传导与抗炎作用和组织稳态相关。此外，TNFRs在CD 8 + T细胞活化中发挥内在作用，揭示了TNF在抗O.恙虫病感染。
Infection with Orientia tsutsugamushi, an obligate intracellular bacterium, can cause mild or severe scrub typhus. Some patients develop acute lung injury, multi-organ failure, and fatal infection; however, little is known regarding key immune mediators that mediate infection control or disease pathogenesis. Using murine models of scrub typhus, we demonstrated in this study the requirement of TNF-TNFR signaling in protective immunity against this infection. Mice lacking both TNF receptors (TNFR1 and TNFR2) were highly susceptible to O. tsutsugamushi infection, displaying significantly increased tissue bacterial burdens and succumbing to infection by day 9, while most wild-type mice survived through day 20. This increased susceptibility correlated with poor activation of cellular immunity in inflamed tissues. Flow cytometry of lung- and spleen-derived cells revealed profound deficiencies in total numbers and activation status of NK cells, neutrophils, and macrophages, as well as CD4 and CD8 T cells. To define the role of individual receptors in O. tsutsugamushi infection, we used mice lacking either TNFR1 or TNFR2. While deficiency in either receptor alone was sufficient to increase host susceptibility to the infection, TNFR1 and TNFR2 played a distinct role in cellular responses. TNF signaling through TNFR1 promoted inflammatory responses and effector T cell expansion, while TNFR2 signaling was associated with anti-inflammatory action and tissue homeostasis. Moreover, TNFRs played an intrinsic role in CD8+ T cell activation, revealing an indispensable role of TNF in protective immunity against O. tsutsugamushi infection.
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