Department of Biotechnology and Bioinformatics, Korea University, Sejong, Korea.
FEBS J. 2017 Oct;284(20):3392-3403. doi: 10.1111/febs.14199. Epub 2017 Aug 30.
Type III-secreted effectors are essential for modulating host immune responses during the pathogenesis of Pseudomonas aeruginosa infections. Little is known about the impact of one of the effectors, ExoY, on inflammasome activation, which results in IL-1β production and pyroptotic cell death. In this study, we found that transcriptional expression of Il-1β was induced to a lesser extent in response to an exoY-harboring strain than to a deleted mutant. This suppressive effect of ExoY was verified by complementation assay as well as by direct translocation of exoY into host cells. In addition to the production of IL-1β, pyroptotic cell death was also diminished in response to an exoY-harboring strain. These inflammasome responses were mediated by the adenylate cyclase activity of ExoY, which plays a role in delaying the activation of NF-κB and caspase-1, a key component of inflammasome-mediated responses. Moreover, the negative effects of ExoY on these responses were in part conferred by the suppression of bacterial motility, which could reduce the degree of bacterial contact with cells. Together, these results demonstrate that the adenylate cyclase activity of P. aeruginosa ExoY can reduce inflammasome-related responses by influencing both the host and the bacterium itself by delaying the activation of inflammatory pathways and suppressing bacterial motility.
III 型分泌效应器对于调节铜绿假单胞菌感染发病过程中的宿主免疫反应至关重要。目前对于其中一种效应器 ExoY 如何影响炎症小体激活，从而导致白细胞介素-1β（IL-1β）产生和细胞焦亡（pyroptotic cell death）的机制知之甚少。在这项研究中，我们发现与缺失突变体相比，含有 exoY 的菌株诱导 Il-1β 转录表达的程度较低。通过互补测定以及将 exoY 直接转染入宿主细胞，证实了 ExoY 的这种抑制作用。除了产生 IL-1β 外，对含有 exoY 的菌株的反应也减少了细胞焦亡。这些炎症小体反应是由 ExoY 的腺苷酸环化酶活性介导的，该活性在延迟核因子-κB（NF-κB）和半胱天冬酶-1（caspase-1）的激活方面发挥作用，后者是炎症小体介导的反应的关键成分。此外，ExoY 对这些反应的负面影响部分归因于细菌运动性的抑制，这可以减少细菌与细胞的接触程度。总之，这些结果表明铜绿假单胞菌 ExoY 的腺苷酸环化酶活性可以通过影响宿主和细菌本身来减少与炎症小体相关的反应，其机制是通过延迟炎症途径的激活和抑制细菌运动性。
