{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T14:32:21Z","timestamp":1776954741147,"version":"3.51.4"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,4,11]],"date-time":"2022-04-11T00:00:00Z","timestamp":1649635200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI 132674, AI 126343, AI 007526 , AI 153586"],"award-info":[{"award-number":["AI 132674, AI 126343, AI 007526 , AI 153586"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Infection with <jats:italic>Orientia tsutsugamushi<\/jats:italic>, 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 <jats:italic>O. tsutsugamushi<\/jats:italic> 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 <jats:italic>O. tsutsugamushi<\/jats:italic> 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<jats:sup>+<\/jats:sup> T cell activation, revealing an indispensable role of TNF in protective immunity against <jats:italic>O. tsutsugamushi<\/jats:italic> infection.<\/jats:p>","DOI":"10.3389\/fimmu.2022.867924","type":"journal-article","created":{"date-parts":[[2022,4,11]],"date-time":"2022-04-11T05:51:45Z","timestamp":1649656305000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":26,"title":["Distinct Role of TNFR1 and TNFR2 in Protective Immunity Against Orientia tsutsugamushi Infection in 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