Alqahtani Maha, Ma Zhuo, Miller Jacob, Yu Jen, Malik Meenakshi, Bakshi Chandra Shekhar
Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY, United States.
Department of Basic and Clinical Sciences, Albany College of Pharmacy and Health Sciences, Albany, NY, United States.
Front Microbiol. 2023 May 17;14:1188112. doi: 10.3389/fmicb.2023.1188112. eCollection 2023.
is a highly virulent Gram-negative bacterium that causes the fatal zoonotic disease tularemia. The mechanisms and signaling pathways leading to the absent in melanoma 2 (Aim2) inflammasome activation have been elegantly elucidated using as a model. Although not pathogenic for humans, . can cause tularemia in mice, and the inflammatory response it triggers is the polar opposite to that observed in mice infected with . strains. This study aimed to understand the mechanisms of Aim2 inflammasome activation in . infected macrophages. The results reveal that macrophages infected with the . live vaccine strain (LVS) induce lower levels of Aim2-dependent IL-1β than those infected with . . The suppression/weak activation of Aim2 in . LVS-infected macrophages is due to the suppression of the cGAS-STING DNA-sensing pathway. Furthermore, the introduction of exogenous . LVS DNA into the cytosol of the . LVS-infected macrophages, alone or in conjunction with a priming signal, failed to restore IL-1β levels similar to those observed for . infected macrophages. These results indicated that, in addition to the bacterial DNA, DNA from some other sources, specifically from the damaged mitochondria, might contribute to the robust Aim2-dependent IL-1β levels observed in . -infected macrophages. The results indicate that . LVS induces mitophagy that may potentially prevent the leakage of mitochondrial DNA and the subsequent activation of the Aim2 inflammasome. Collectively, this study demonstrates that the mechanisms of Aim2 inflammasome activation established for . are not operative in . .
是一种高毒力革兰氏阴性细菌，可导致致命的人畜共患病兔热病。使用作为模型，已巧妙地阐明了导致黑色素瘤2（Aim2）炎性小体激活的机制和信号通路。虽然对人类无致病性，但。可在小鼠中引起兔热病，其引发的炎症反应与感染。菌株的小鼠中观察到的炎症反应截然相反。本研究旨在了解感染。的巨噬细胞中Aim2炎性小体激活的机制。结果显示，感染。活疫苗株（LVS）的巨噬细胞诱导的Aim2依赖性白细胞介素-1β水平低于感染。的巨噬细胞。在感染。LVS的巨噬细胞中，Aim2的抑制/弱激活是由于cGAS-STING DNA传感途径的抑制。此外，将外源性。LVS DNA单独或与启动信号一起引入感染。LVS的巨噬细胞的细胞质中，未能恢复与感染。的巨噬细胞中观察到的白细胞介素-1β水平相似的水平。这些结果表明，除了细菌DNA外，来自其他一些来源的DNA，特别是来自受损线粒体的DNA，可能有助于在感染。的巨噬细胞中观察到的强大的Aim2依赖性白细胞介素-1β水平。结果表明，。LVS诱导线粒体自噬，这可能潜在地防止线粒体DNA泄漏和随后的Aim2炎性小体激活。总的来说，这项研究表明，为。建立的Aim2炎性小体激活机制在。中不起作用。
