Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United States.
Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, United States.
Front Immunol. 2022 Apr 11;13:867924. doi: 10.3389/fimmu.2022.867924. eCollection 2022.
Infection with , 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 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 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 infection.
感染恙虫病东方体，一种专性细胞内细菌，可能导致轻度或重度恙虫病。一些患者会发展为急性肺损伤、多器官衰竭和致命感染；然而，对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。在恙虫病的小鼠模型中，我们在这项研究中证明了 TNF-TNFR 信号在针对这种感染的保护性免疫中的必要性。缺乏两种 TNF 受体（TNFR1 和 TNFR2）的小鼠对感染高度敏感，组织细菌负荷显著增加，并在第 9 天死于感染，而大多数野生型小鼠在第 20 天之前存活。这种易感性的增加与炎症组织中细胞免疫的激活不良相关。对肺和脾来源的细胞进行流式细胞术分析显示，NK 细胞、中性粒细胞和巨噬细胞以及 CD4 和 CD8 T 细胞的总数和激活状态存在严重缺陷。为了确定单个受体在感染中的作用，我们使用了缺乏 TNFR1 或 TNFR2 的小鼠。尽管单独缺乏任何一种受体就足以增加宿主对感染的易感性，但 TNFR1 和 TNFR2 在细胞反应中发挥了不同的作用。TNFR1 介导的 TNF 信号促进炎症反应和效应 T 细胞扩增，而 TNFR2 信号与抗炎作用和组织稳态有关。此外，TNFRs 在 CD8 T 细胞激活中发挥内在作用，揭示了 TNF 在保护性免疫中对感染的不可或缺作用。
