Antigen-encapsulating host extracellular vesicles derived from Salmonella-infected cells stimulate pathogen-specific Th1-type responses in vivo.
Antigen-encapsulating host extracellular vesicles derived from Salmonella-infected cells stimulate pathogen-specific Th1-type responses in vivo.
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DOI：
10.1371/journal.ppat.1009465
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发表时间：
2021-05
期刊：
影响因子：
6.7
通讯作者：
Ferraro MJ
中科院分区：
文献类型：
--
作者：
Hui WW;Emerson LE;Clapp B;Sheppe AE;Sharma J;Del Castillo J;Ou M;Maegawa GHB;Hoffman C;Larkin Iii J;Pascual DW;Ferraro MJ
鼠伤寒沙门氏菌是一种非伤寒沙门氏菌病的病原体，缺乏临床批准的人类疫苗。沙门氏菌是一种胞内病原菌，影响多种细胞途径。然而，由宿主来源的小细胞外囊泡（ev）（如外泌体）促进的细胞间通讯机制是宿主对这种感染反应的一个被忽视的方面。我们对来自沙门氏菌感染巨噬细胞的外泌体进行了全面的基于蛋白质组的网络分析，以确定通过这些ev运输的宿主分子。该分析预测，在巨噬细胞感染过程中产生的宿主源性小ev刺激巨噬细胞并促进T辅助1 （Th1）细胞的活化。我们发现在感染过程中产生的外泌体含有沙门氏菌蛋白，包括先前在小鼠研究中显示的刺激针对沙门氏菌的保护性免疫反应的独特抗原。此外，我们发现感染后形成的宿主ev在经鼻给BALB/c小鼠时刺激了针对沙门氏菌感染的粘膜免疫反应，这是一种已知的启动粘膜免疫的抗原给药途径。具体来说，给动物注射这些囊泡刺激了抗沙门氏菌IgG抗体的产生，如抗ompa抗体。外泌体也刺激抗原特异性细胞介导的免疫。特别是，从小鼠分离的脾单核细胞与沙门氏菌感染的抗原呈递细胞衍生的外泌体一起使用，可以增加CD4+ T细胞分泌th1型细胞因子，以响应沙门氏菌抗原。这些结果表明，在感染过程中形成的小ev有助于Th1细胞在抗沙门氏菌反应中的偏倚。总的来说，这项研究有助于揭示宿主来源的小ev作为传递抗原的载体的作用，以诱导针对革兰氏阴性菌的th1型免疫。了解ev介导的防御机制将有助于开发未来对抗细菌感染的方法。鼠伤寒沙门氏菌是一种非伤寒沙门氏菌病的病原体，我们仍然缺乏临床批准的针对这种感染的疫苗。设计有效的沙门氏菌疫苗可以从研究宿主对这种病原体的免疫反应中被忽视的方面获益。纳米细胞外囊泡（EVs）促进细胞间的通信可以影响免疫反应。我们早期的工作表明，沙门氏菌感染导致巨噬细胞产生免疫原性小ev。在这里，我们对EV货物进行了蛋白质组学和代谢组学分析，结果表明由沙门氏菌感染的巨噬细胞产生的EV刺激巨噬细胞并促进t -辅助性1 （Th1）细胞活化。我们在体内证实，在BALB/c小鼠中，这些ev的粘膜给药促进了对沙门氏菌感染的粘膜免疫反应。来自感染巨噬细胞的ev增加了CD4+ T细胞分泌IL-2、IFN-γ和TNF-α，以响应沙门氏菌抗原，导致Th1细胞偏倚。这些ev不仅刺激了抗原特异性细胞介导的免疫，而且还促进了抗沙门氏菌抗体的产生，其中包括识别ev中存在的细菌蛋白的igg。我们的研究揭示了ev作为传递抗原的载体的新作用，从而诱导针对革兰氏阴性菌的th1型免疫，从而支持未来对抗沙门氏菌感染的预防性方法的发展。
Salmonella Typhimurium is a causative agent of nontyphoidal salmonellosis, for which there is a lack of a clinically approved vaccine in humans. As an intracellular pathogen, Salmonella impacts many cellular pathways. However, the intercellular communication mechanism facilitated by host-derived small extracellular vesicles (EVs), such as exosomes, is an overlooked aspect of the host responses to this infection. We used a comprehensive proteome-based network analysis of exosomes derived from Salmonella-infected macrophages to identify host molecules that are trafficked via these EVs. This analysis predicted that the host-derived small EVs generated during macrophage infection stimulate macrophages and promote activation of T helper 1 (Th1) cells. We identified that exosomes generated during infection contain Salmonella proteins, including unique antigens previously shown to stimulate protective immune responses against Salmonella in murine studies. Furthermore, we showed that host EVs formed upon infection stimulate a mucosal immune response against Salmonella infection when delivered intranasally to BALB/c mice, a route of antigen administration known to initiate mucosal immunity. Specifically, the administration of these vesicles to animals stimulated the production of anti-Salmonella IgG antibodies, such as anti-OmpA antibodies. Exosomes also stimulated antigen-specific cell-mediated immunity. In particular, splenic mononuclear cells isolated from mice administered with exosomes derived from Salmonella-infected antigen-presenting cells increased CD4+ T cells secreting Th1-type cytokines in response to Salmonella antigens. These results demonstrate that small EVs, formed during infection, contribute to Th1 cell bias in the anti-Salmonella responses. Collectively, this study helps to unravel the role of host-derived small EVs as vehicles transmitting antigens to induce Th1-type immunity against Gram-negative bacteria. Understanding the EV-mediated defense mechanisms will allow the development of future approaches to combat bacterial infections. Salmonella Typhimurium is a causative agent of nontyphoidal salmonellosis, and we still lack a clinically approved vaccine against this infection. The design of efficacious vaccines against Salmonella can benefit from studying overlooked aspects of host immune responses to this pathogen. The cell-to-cell communication facilitated by nano-sized extracellular vesicles (EVs) can affect the immune response. Our earlier work showed that Salmonella infection leads to the generation of immunogenic small EVs by macrophages. Here, we performed a proteomic and metabolomic analysis of the EV cargo, which indicated that EVs generated by Salmonella-infected macrophages stimulate macrophages and promote T-helper 1 (Th1) cell activation. We confirmed in vivo that mucosal administration of these EVs promotes a mucosal immune response against Salmonella infection in BALB/c mice. EVs from infected macrophages increased the CD4+ T cells secreting IL-2, IFN-γ, and TNF-α in response to Salmonella antigens, contributing to Th1 cell bias. These EVs not only stimulated antigen-specific cell-mediated immunity, but also contributed to anti-Salmonella antibody production, which included IgGs recognizing bacterial proteins present in EVs. Our study unraveled a novel role of EVs as vehicles transmitting antigens to induce Th1-type immunity against Gram-negative bacteria, thus supporting the future development of preventative approaches to combat Salmonella infection.
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影响因子：
12.2
作者：
Corthesy, Blaise;Bioley, Gilles
通讯作者：
Bioley, Gilles
影响因子：
46.9
作者：
Alvarez-Erviti, Lydia;Seow, Yiqi;Wood, Matthew J. A.
通讯作者：
Wood, Matthew J. A.
DOI：
10.1073/pnas.1521230113
发表时间：
2016-02-23
影响因子：
11.1
作者：
Kowal, Joanna;Arras, Guillaume;Thery, Clotilde
通讯作者：
Thery, Clotilde
影响因子：
6.4
作者：
Konadu, Kateena Addae;Chu, Jane;Bond, Vincent C.
通讯作者：
Bond, Vincent C.
DOI：
10.1083/jcb.200508014
发表时间：
2006-03-13
期刊：
The Journal of cell biology
影响因子：
--
作者：
Booth AM;Fang Y;Fallon JK;Yang JM;Hildreth JE;Gould SJ
通讯作者：
Gould SJ