TolC and EmrA1 contribute to Francisella novicida multidrug resistance and modulation of host cell death.

IF 2.7 3区 生物学 Q3 MICROBIOLOGY Journal of Bacteriology Pub Date : 2024-09-19 Epub Date: 2024-08-28 DOI:10.1128/jb.00246-24
Erik J Kopping, P Todd Benziger, David G Thanassi
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Abstract

Francisella spp. are Gram-negative, facultative intracellular pathogens. Francisella tularensis causes the human disease tularemia and is considered a biological threat agent due to its high infectivity and virulence. A central aspect of Francisella virulence is its ability to dampen host immune responses. We previously identified the outer membrane channel (OMC) protein TolC as a critical F. tularensis virulence factor required for suppression of apoptotic and proinflammatory responses during macrophage infection. TolC functions as part of multidrug efflux systems and the type I secretion pathway that exports bacterial effector proteins. In these systems, TolC forms tripartite complexes together with an inner membrane transporter and periplasmic membrane fusion protein (MFP). To advance understanding of TolC function in Francisella, we analyzed OMC and MFP homologs in Francisella novicida, a widely used model species that causes a tularemia-like disease in mice. In agreement with the previous F. tularensis studies, all three OMCs present in F. novicida contributed to multidrug resistance, but only TolC was important for suppressing macrophage cell death. In addition, we identified the EmrA1 MFP as important for resisting antimicrobial compounds and dampening host cell death. In contrast to results obtained with F. tularensis, the cell death triggered during infection with the F. novicida tolC and emrA1 mutants was dominated by pyroptosis rather than apoptosis. These data expand our understanding of TolC function in Francisella and underscore both conserved and differential aspects of F. novicida and F. tularensis.

Importance: Francisella tularensis is a Gram-negative intracellular bacterial pathogen and causative agent of tularemia. We previously identified the outer membrane channel protein TolC as contributing to antimicrobial resistance and subversion of host responses by F. tularensis. To advance understanding of TolC function in Francisella and to identify components that might work together with TolC, we took advantage of a transposon mutant library in F. novicida, a model species that causes a tularemia-like disease in mice. Our findings identify TolC and the membrane fusion protein EmrA1 as important for both antimicrobial resistance and suppression of macrophage cell death. This study also revealed differences in cell death pathways triggered by F. novicida versus F. tularensis infection that may relate to differences in virulence.

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TolC和EmrA1有助于新弗朗西斯菌的多药耐药性和宿主细胞的死亡调节。
弗朗西斯菌属是革兰氏阴性、细胞内兼性病原体。土拉菌属弗朗西斯菌会导致人类患上土拉菌病,并因其高度传染性和毒力而被认为是一种生物威胁病原体。弗朗西斯菌毒力的一个核心方面是其抑制宿主免疫反应的能力。我们之前发现,外膜通道(OMC)蛋白 TolC 是一种关键的土拉菌毒力因子,在巨噬细胞感染过程中抑制凋亡和促炎反应。TolC 是多药外流系统和 I 型分泌途径的一部分,该途径可输出细菌效应蛋白。在这些系统中,TolC 与内膜转运体和外质膜融合蛋白(MFP)一起形成三方复合物。为了进一步了解 TolC 在弗朗西斯菌中的功能,我们分析了新弗朗西斯菌中的 OMC 和 MFP 同源物。与之前的土拉菌研究一致,新弗朗西斯菌中存在的所有三种 OMC 都对多药耐药性有贡献,但只有 TolC 对抑制巨噬细胞死亡有重要作用。此外,我们还发现 EmrA1 MFP 对抵抗抗菌化合物和抑制宿主细胞死亡非常重要。与土拉菌感染的结果不同,诺瓦克氏菌 TolC 和 EmrA1 突变体在感染过程中引发的细胞死亡主要是热凋亡,而不是细胞凋亡。这些数据拓展了我们对 TolC 在弗朗西斯菌中功能的理解,并强调了 F. novicida 和 F. tularensis 的保守性和差异性:重要意义:土拉弗氏菌是一种革兰氏阴性细胞内细菌病原体,也是土拉菌病的致病菌。我们以前曾发现外膜通道蛋白 TolC 是导致土拉弗氏菌产生抗菌性和颠覆宿主反应的原因。为了进一步了解 TolC 在弗朗西斯菌中的功能,并确定可能与 TolC 共同作用的成分,我们利用了诺维菌的转座子突变体库。我们的研究结果发现,TolC和膜融合蛋白EmrA1对抗菌性和抑制巨噬细胞死亡都很重要。这项研究还揭示了诺维卡氏菌与土拉菌感染所引发的细胞死亡途径的差异,这可能与毒力差异有关。
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来源期刊
Journal of Bacteriology
Journal of Bacteriology 生物-微生物学
CiteScore
6.10
自引率
9.40%
发文量
324
审稿时长
1.3 months
期刊介绍: The Journal of Bacteriology (JB) publishes research articles that probe fundamental processes in bacteria, archaea and their viruses, and the molecular mechanisms by which they interact with each other and with their hosts and their environments.
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