ER-transiting bacterial toxins amplify STING innate immune responses and elicit ER stress.

IF 2.9 3区 医学 Q3 IMMUNOLOGY
Infection and Immunity Pub Date : 2024-08-13 Epub Date: 2024-07-26 DOI:10.1128/iai.00300-24
Catherine Schlenker, Katharina Richard, Sofia Skobelkina, R Paige Mathena, Darren J Perkins
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引用次数: 0

Abstract

The cGAS/STING sensor system drives innate immune responses to intracellular microbial double-stranded DNA (dsDNA) and bacterial cyclic nucleotide second messengers (e.g., c-di-AMP). STING-dependent cell-intrinsic responses can increase resistance to microbial infection and speed pathogen clearance. Correspondingly, STING activation and signaling are known to be targeted for suppression by effectors from several bacterial pathogens. Whether STING responses are also positively regulated through sensing of specific bacterial effectors is less clear. We find that STING activation through dsDNA, by its canonical ligand 2'-3' cGAMP, or the small molecule DMXAA is potentiated following intracellular delivery of the AB5 toxin family member pertussis toxin from Bordetella pertussis or the B subunit of cholera toxin from Vibrio cholerae. Entry of pertussis toxin or cholera toxin B into mouse macrophages triggers markers of endoplasmic reticulum (ER) stress and enhances ligand-dependent STING responses at the level of STING receptor activation in a manner that is independent of toxin enzymatic activity. Our results provide an example in which STING responses integrate information about the presence of relevant ER-transiting bacterial toxins into the innate inflammatory response and may help to explain the in vivo adjuvant effects of catalytically inactive toxins.

ER转运细菌毒素会放大STING先天性免疫反应并引发ER应激。
cGAS/STING 传感系统驱动细胞内微生物双链 DNA(dsDNA)和细菌环核苷酸第二信使(如 c-di-AMP)的先天免疫反应。STING 依赖性细胞内在反应可增强对微生物感染的抵抗力,加快病原体的清除。相应地,已知 STING 的激活和信号传导会被几种细菌病原体的效应物抑制。至于 STING 反应是否也会通过感知特定细菌效应物而受到正向调控,目前还不太清楚。我们发现,在细胞内输送百日咳杆菌的 AB5 毒素家族成员百日咳毒素或霍乱弧菌的霍乱毒素 B 亚基后,STING 通过 dsDNA、其规范配体 2'-3' cGAMP 或小分子 DMXAA 被激活。百日咳毒素或霍乱毒素 B 进入小鼠巨噬细胞会触发内质网(ER)应激标记,并在 STING 受体活化水平上增强配体依赖性 STING 反应,而这种方式与毒素酶活性无关。我们的研究结果提供了一个实例,说明 STING 反应将有关 ER 转运细菌毒素存在的信息整合到先天性炎症反应中,并可能有助于解释催化活性毒素的体内佐剂效应。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Infection and Immunity
Infection and Immunity 医学-传染病学
CiteScore
6.00
自引率
6.50%
发文量
268
审稿时长
3 months
期刊介绍: Infection and Immunity (IAI) provides new insights into the interactions between bacterial, fungal and parasitic pathogens and their hosts. Specific areas of interest include mechanisms of molecular pathogenesis, virulence factors, cellular microbiology, experimental models of infection, host resistance or susceptibility, and the generation of innate and adaptive immune responses. IAI also welcomes studies of the microbiome relating to host-pathogen interactions.
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