Human MAIT cell cytolytic effector proteins synergize to overcome carbapenem resistance in Escherichia coli
Human MAIT cell cytolytic effector proteins synergize to overcome carbapenem resistance in Escherichia coli
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DOI：
10.1371/journal.pbio.3000644
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发表时间：
2020-06-01
期刊：
影响因子：
9.8
通讯作者：
Leeansyah, Edwin
中科院分区：
文献类型：
--
作者：
Boulouis, Caroline;Sia, Wan Rong;Leeansyah, Edwin
粘膜相关不变T（MAIT）细胞是人体中丰富的抗微生物T细胞，并识别源自MHC-Ib相关蛋白（MR 1）呈现的微生物核黄素生物合成途径的抗原。然而，负责MAIT细胞抗微生物活性的机制尚未完全理解，并且尚未探索这些机制对抗生素耐药细菌的功效。在这里，我们表明，MAIT细胞介导的MR 1限制的抗大肠杆菌临床菌株的抗菌活性的方式依赖于溶细胞蛋白的活性，但独立于生产的促炎细胞因子或诱导受感染的细胞凋亡。孔形成抗微生物蛋白颗粒溶素和丝氨酸蛋白酶颗粒酶B的联合作用响应于T细胞受体（TCR）介导的MR 1呈递抗原的识别而释放，对于介导对细胞相关和自由生活的胞外形式的E.杆菌此外，MAIT细胞介导的细菌控制扩展到多药耐药E。大肠杆菌的主要临床分离株对碳青霉烯类抗生素（一种最后的抗生素）具有额外的耐药性。值得注意的是，MAIT细胞分泌物中高水平的颗粒溶素和颗粒酶B通过增加细菌细胞的渗透性直接损伤细菌细胞，使最初的耐药E.对碳青霉烯类杀菌活性敏感的大肠杆菌。这些发现明确了溶细胞效应蛋白在MAIT细胞介导的抗菌活性中的作用，并表明颗粒溶素和颗粒酶B协同作用恢复了碳青霉烯类杀菌活性，克服了大肠杆菌对碳青霉烯类的耐药性。杆菌
Mucosa-associated invariant T (MAIT) cells are abundant antimicrobial T cells in humans and recognize antigens derived from the microbial riboflavin biosynthetic pathway presented by the MHC-Ib-related protein (MR1). However, the mechanisms responsible for MAIT cell antimicrobial activity are not fully understood, and the efficacy of these mechanisms against antibiotic resistant bacteria has not been explored. Here, we show that MAIT cells mediate MR1-restricted antimicrobial activity against Escherichia coli clinical strains in a manner dependent on the activity of cytolytic proteins but independent of production of pro-inflammatory cytokines or induction of apoptosis in infected cells. The combined action of the pore-forming antimicrobial protein granulysin and the serine protease granzyme B released in response to T cell receptor (TCR)-mediated recognition of MR1-presented antigen is essential to mediate control against both cell-associated and free-living, extracellular forms of E. coli. Furthermore, MAIT cell-mediated bacterial control extends to multidrug-resistant E. coli primary clinical isolates additionally resistant to carbapenems, a class of last resort antibiotics. Notably, high levels of granulysin and granzyme B in the MAIT cell secretomes directly damage bacterial cells by increasing their permeability, rendering initially resistant E. coli susceptible to the bactericidal activity of carbapenems. These findings define the role of cytolytic effector proteins in MAIT cell-mediated antimicrobial activity and indicate that granulysin and granzyme B synergize to restore carbapenem bactericidal activity and overcome carbapenem resistance in E. coli.