The Citrobacter rodentium type III secretion system effector EspO affects mucosal damage repair and antimicrobial responses.
The Citrobacter rodentium type III secretion system effector EspO affects mucosal damage repair and antimicrobial responses.
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III型柠檬酸杆菌分泌系统效应子ESPO影响粘膜损伤修复和抗菌反应。
DOI：
10.1371/journal.ppat.1007406
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发表时间：
2018-10
期刊：
影响因子：
6.7
通讯作者：
Frankel G
中科院分区：
文献类型：
--
作者：
Berger CN;Crepin VF;Roumeliotis TI;Wright JC;Serafini N;Pevsner-Fischer M;Yu L;Elinav E;Di Santo JP;Choudhary JS;Frankel G
啮齿类柠檬酸杆菌的感染引发了强烈的组织损伤修复反应，表现为IL-22的分泌，在没有IL-22的情况下，小鼠死于感染。C的主要特征之一。啮齿类感染的主要原因是结肠隐窝增生（CCH）和生态失调。为了在宿主体内定殖并与肠道菌群竞争，C。啮齿动物采用III型分泌系统（T3 SS），其将效应物注入结肠肠上皮细胞（IEC）。一旦被注射，效应物破坏参与先天免疫应答、细胞代谢和粘膜氧合的过程。重要的是，触发组织修复反应的效应物的身份是未知的。在这里，我们报告了效应EspO，在志贺氏菌属中发现的OspE的直向同源物，影响C后8天和14天的IEC增殖。啮齿类感染以及从结肠外植体分泌IL-22。虽然我们没有观察到第3组先天性淋巴细胞（ILC 3）和T细胞的募集差异，但它们是C.在啮齿动物感染中，ΔespO感染的特征在于粘膜下嗜中性粒细胞的募集减少，这与IEC中Mmp 9和趋化因子（例如S100 a8/9）的丰度较低相一致。此外，与感染WT C的小鼠相比，感染ΔespO的小鼠触发显著更少的营养免疫（例如钙卫蛋白，Lcn 2）和抗菌肽（Reg 3 β，Reg 3 γ）的表达。啮齿动物。这与IEC中STAT 3磷酸化的减少重叠。重要的是，虽然ΔespO感染期间CCH减少和抗菌蛋白丰度不影响C.啮齿类定殖或嗜酸性变形菌门的组成，它们对厚壁菌门亚群有微妙的影响。EspO是第一个影响中性粒细胞募集和IL-22分泌以及IEC中抗菌和营养免疫蛋白表达的细菌毒力因子。啮齿柠檬酸杆菌是研究病原体-宿主-微生物组相互作用的金标准模型。C语言的两个特点是：啮齿类感染是结肠损伤修复反应和结肠炎;与人类炎症性肠病共有的症状。导致组织损伤修复反应的过程和涉及的细菌毒力因子仍然是难以捉摸的。在本文中，我们表明，C。啮齿类III型分泌系统效应子EspO在引发损伤愈合反应、中性粒细胞向结肠绒毛的募集、IL-22从结肠外植体的分泌和IL-22调节基因在肠上皮细胞中的表达中起主要作用。本文首次报道了一种影响肠上皮细胞增殖和免疫反应的细菌毒力因子。
Infection with Citrobacter rodentium triggers robust tissue damage repair responses, manifested by secretion of IL-22, in the absence of which mice succumbed to the infection. Of the main hallmarks of C. rodentium infection are colonic crypt hyperplasia (CCH) and dysbiosis. In order to colonize the host and compete with the gut microbiota, C. rodentium employs a type III secretion system (T3SS) that injects effectors into colonic intestinal epithelial cells (IECs). Once injected, the effectors subvert processes involved in innate immune responses, cellular metabolism and oxygenation of the mucosa. Importantly, the identity of the effector/s triggering the tissue repair response is/are unknown. Here we report that the effector EspO ,an orthologue of OspE found in Shigella spp, affects proliferation of IECs 8 and 14 days post C. rodentium infection as well as secretion of IL-22 from colonic explants. While we observed no differences in the recruitment of group 3 innate lymphoid cells (ILC3s) and T cells, which are the main sources of IL-22 at the early and late stages of C. rodentium infection respectively, infection with ΔespO was characterized by diminished recruitment of sub-mucosal neutrophils, which coincided with lower abundance of Mmp9 and chemokines (e.g. S100a8/9) in IECs. Moreover, mice infected with ΔespO triggered significantly lesser nutritional immunity (e.g. calprotectin, Lcn2) and expression of antimicrobial peptides (Reg3β, Reg3γ) compared to mice infected with WT C. rodentium. This overlapped with a decrease in STAT3 phosphorylation in IECs. Importantly, while the reduced CCH and abundance of antimicrobial proteins during ΔespO infection did not affect C. rodentium colonization or the composition of commensal Proteobacteria, they had a subtle consequence on Firmicutes subpopulations. EspO is the first bacterial virulence factor that affects neutrophil recruitment and secretion of IL-22, as well as expression of antimicrobial and nutritional immunity proteins in IECs. Citrobacter rodentium is a gold standard model to study pathogen-host-microbiome interactions. Two of the hallmarks of C. rodentium infection are colonic damage repair responses and colitis; symptoms that are shared with inflammatory bowel diseases in humans. The processes leading to tissue damage repair responses and the implicated bacterial virulence factors are still elusive. In this paper, we show that the C. rodentium type III secretion system effector EspO plays a major role in triggering damage healing responses, recruitment of neutrophils to the colonic villi, secretion of IL-22 from colonic explants and expression of IL-22 regulated genes in intestinal epithelial cells. This paper is the first to report a bacterial virulence factor that impacts on both intestinal epithelial cell proliferation and immune responses.
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DOI：
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发表时间：
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