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To date, the molecular mechanisms of the interactions between <jats:italic>C. perfringens<\/jats:italic> and the host remain poorly understood. Here, we show that stimulator of interferon genes (STING)-dependent trained immunity protected against <jats:italic>C. perfringens<\/jats:italic> infection through mTOR signaling. Heat-killed <jats:italic>Candida albicans<\/jats:italic> (HKCA) training elicited elevated TNF-\u03b1 and IL-6 production after LPS restimulation in mouse peritoneal macrophages (PM). Although HKCA-trained PM produced decreased levels of TNF-\u03b1 and IL-6, the importance of trained immunity was demonstrated by the fact that HKCA training resulted in enhanced bacterial phagocytic ability and clearance in vivo and in vitro during <jats:italic>C. perfringens<\/jats:italic> infection. Interestingly, HKCA training resulted in the activation of STING signaling. We further demonstrate that STING agonist DMXAA is a strong inducer of trained immunity and conferred host resistance to <jats:italic>C. perfringens<\/jats:italic> infection in PM. Importantly, corresponding to higher bacterial burden, reduction in cytokine secretion, phagocytosis, and bacterial killing were shown in the absence of STING after HKCA training. Meanwhile, the high expression levels of AKT\/mTOR\/HIF1\u03b1 were indeed accompanied by an activated STING signaling under HKCA or DMXAA training. Moreover, inhibiting mTOR signaling with rapamycin dampened the trained response to LPS and <jats:italic>C. perfringens<\/jats:italic> challenge in wild-type (WT) PM after HKCA training<jats:italic>.<\/jats:italic> Furthermore, STING\u2011deficient PM presented decreased levels of mTOR signaling-related proteins. Altogether, these results support STING involvement in trained immunity which protects against <jats:italic>C. perfringens<\/jats:italic> infection via mTOR signaling.<\/jats:p>","DOI":"10.1186\/s13567-024-01301-1","type":"journal-article","created":{"date-parts":[[2024,4,15]],"date-time":"2024-04-15T10:02:09Z","timestamp":1713175329000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["STING-dependent trained immunity contributes to host defense against Clostridium perfringens infection via mTOR signaling"],"prefix":"10.1186","volume":"55","author":[{"given":"Zhen-Zhen","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Kai","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Qi","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue-Yue","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-Bao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-Gang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"An","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5294-9790","authenticated-orcid":false,"given":"Yong-Jun","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,4,15]]},"reference":[{"key":"1301_CR1","doi-asserted-by":"publisher","first-page":"1250684","DOI":"10.1126\/science.1250684","volume":"345","author":"SC Cheng","year":"2014","unstructured":"Cheng SC, Quintin J, Cramer RA, Shepardson KM, Saeed S, Kumar V, Giamarellos-Bourboulis EJ, Martens JH, Rao NA, Aghajanirefah A, Manjeri GR, Li Y, Ifrim DC, Arts RJ, van der Veer BM, Deen PM, Logie C, O\u2019Neill LA, Willems P, van de Veerdonk FL, van der Meer JW, Ng A, Joosten LA, Wijmenga C, Stunnenberg HG, Xavier RJ, Netea MG (2014) mTOR- and HIF-1\u03b1-mediated aerobic glycolysis as metabolic basis for trained immunity. 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