Zhang Yusi, Liu He, Liu Dalu, Zhang Huiyuan, Ma Ying, Li Na, Zhang Chunmei, Xue Manling, Wang Fenglan, Jia Xiaozhou, Zhang Hui, Tang Kang, Xu Xiaoyue, Wang Shijia, Wei Yiwen, Yang Xiaojing, Zuo Jiajia, Chen Lihua, Jin Boquan, Zhang Yun
Department of Immunology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China.
Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China.
Commun Biol. 2025 Apr 1;8(1):538. doi: 10.1038/s42003-025-07979-z.
Hantaan virus (HTNV) triggers an epidemic of hemorrhagic fever with renal syndrome (HFRS), which is predominantly prevalent in Asia. Mucosal-associated invariant T (MAIT) cells, categorized as innate-like T lymphocytes, perform crucial functions in the innate host defense mechanism during virus infection. We previously showed that MAIT cells played antiviral roles in vitro. But marked reduction of MAIT cells was present in the peripheral blood of HFRS patients. Till now, the role of MAIT cells in vivo and the mechanisms of HTNV-induced the MAIT cell deficiency have not yet been fully explored. In this study, by combining the clinical samples, MAIT deficiency mice and in vitro infected MAIT cell models, we find that pyroptosis was the main reason of MAIT cell loss in the peripheral blood of HFRS patients. The molecular mechanisms are related to the overload of calcium in the endoplasmic reticulum (ER) of MAIT cells, which subsequently induces inosital-requiring enzyme-1α (IRE1α)-mediated ER-stress and following pyroptosis. ER-stress inhibitor can reverse the pyroptosis of MAIT cells during HTNV infection. In conclusion, this study firstly reveals the underlying molecular mechanisms for the deficiency of MAIT cells during HTNV infection, and suggests a potential way to stabilize the MAIT cells population in HFRS.
汉坦病毒（HTNV）引发肾综合征出血热（HFRS）的流行，该病主要在亚洲流行。黏膜相关恒定T（MAIT）细胞属于固有样T淋巴细胞，在病毒感染期间的固有宿主防御机制中发挥关键作用。我们之前表明MAIT细胞在体外发挥抗病毒作用。但HFRS患者外周血中MAIT细胞明显减少。到目前为止，MAIT细胞在体内的作用以及HTNV诱导MAIT细胞缺乏的机制尚未得到充分探索。在本研究中，通过结合临床样本、MAIT细胞缺陷小鼠和体外感染MAIT细胞模型，我们发现细胞焦亡是HFRS患者外周血中MAIT细胞丢失的主要原因。分子机制与MAIT细胞内质网（ER）中钙超载有关，随后诱导肌醇需求酶-1α（IRE1α）介导的内质网应激及随后的细胞焦亡。内质网应激抑制剂可逆转HTNV感染期间MAIT细胞的细胞焦亡。总之，本研究首次揭示了HTNV感染期间MAIT细胞缺乏的潜在分子机制，并提出了一种稳定HFRS中MAIT细胞群体的潜在方法。
