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Helicobacter pylori actively suppresses innate immune nucleic acid receptors
Gut Microbes ( IF 12.2 ) Pub Date : 2022-07-29 , DOI: 10.1080/19490976.2022.2105102
Samuel D R Dooyema 1, 2 , Jennifer M Noto 3 , Lydia E Wroblewski 3 , M Blanca Piazuelo 3 , Uma Krishna 3 , Giovanni Suarez 3 , Judith Romero-Gallo 3 , Alberto G Delgado 3 , Richard M Peek 1, 3
Affiliation  

ABSTRACT

Chronic mucosal pathogens have evolved multiple strategies to manipulate the host immune response; consequently, microbes contribute to the development of >2 million cases of cancer/year. Gastric adenocarcinoma is the fourth leading cause of cancer-related death and Helicobacter pylori confers the highest risk for this disease. Gastric innate immune effectors can either eliminate bacteria or mobilize adaptive immune responses including Toll-like receptors (TLRs), and cytosolic DNA sensor/adaptor proteins (e.g., stimulator of interferon genes, STING). The H. pylori strain-specific cag type IV secretion system (T4SS) augments gastric cancer risk and translocates DNA into epithelial cells where it activates the microbial DNA sensor TLR9 and suppresses injury in vivo; however, the ability of H. pylori to suppress additional nucleic acid PRRs within the context of chronic gastric inflammation and injury remains undefined. In this study, in vitro and ex vivo experiments identified a novel mechanism through which H. pylori actively suppresses STING and RIG-I signaling via downregulation of IRF3 activation. In vivo, the use of genetically deficient mice revealed that Th17 inflammatory responses are heightened following H. pylori infection within the context of Sting deficiency in conjunction with increased expression of a known host immune regulator, Trim30a. This novel mechanism of immune suppression by H. pylori is likely a critical component of a finely tuned rheostat that not only regulates the initial innate immune response, but also drives chronic gastric inflammation and injury.



中文翻译:

幽门螺杆菌主动抑制先天免疫核酸受体

摘要

慢性黏膜病原体已经进化出多种策略来操纵宿主免疫反应;因此,微生物导致每年超过 200 万例癌症的发生。胃腺癌是癌症相关死亡的第四大原因,幽门螺杆菌是这种疾病的最高风险。胃先天免疫效应器可以消除细菌或调动适应性免疫反应,包括 Toll 样受体 (TLR) 和细胞溶质 DNA 传感器/适配蛋白(例如,干扰素基因刺激物,STING)。H. pylori菌株特异性cag IV 型分泌系统 (T4SS) 增加了胃癌的风险并将 DNA 转移到上皮细胞中,在那里它激活微生物 DNA 传感器 TLR9 并抑制损伤体内; 然而,幽门螺杆菌在慢性胃炎症和损伤的情况下抑制额外核酸 PRR 的能力仍未确定。在这项研究中,体外离体实验确定了一种新机制,幽门螺杆菌通过该机制通过下调 IRF3 激活来主动抑制 STING 和 RIG-I 信号传导。在体内,基因缺陷小鼠的使用表明,Th17 炎症反应在H. pylori感染后在Sting环境中增强。缺乏与已知宿主免疫调节剂Trim30a的表达增加有关。幽门螺杆菌的这种新的免疫抑制机制可能是微调变阻器的关键组成部分,它不仅可以调节最初的先天免疫反应,还可以驱动慢性胃部炎症和损伤。

更新日期:2022-07-30
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