Conserved metabolic regulator ArcA responds to oxygen availability, iron limitation, and cell envelope perturbations during bacteremia.
Conserved metabolic regulator ArcA responds to oxygen availability, iron limitation, and cell envelope perturbations during bacteremia.
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保守的代谢调节因子ArcA在菌血症期间对氧气可利用性、铁限制以及细胞膜扰动作出反应。
DOI：
10.1128/mbio.01448-23
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发表时间：
2023-10-31
期刊：
影响因子：
6.4
通讯作者：
Mobley, Harry L. T.
中科院分区：
文献类型：
--
作者：
Brown, Aric N.;Anderson, Mark T.;Smith, Sara N.;Bachman, Michael A.;Mobley, Harry L. T.
革兰氏阴性兼性厌氧菌常引起菌血症，这是一种与严重临床结果相关的全身感染。ArcAB是一个抑制有氧呼吸的双组分调节系统，是这类细菌代谢适应的关键介质。利用全球遗传筛选的靶向突变分析，我们在小鼠菌血症模型中确定了arcA基因促进弗氏柠檬酸杆菌、肺炎克雷伯菌和粘质沙雷菌的适应性，但不促进大肠杆菌的适应性。arcA突变体对细菌细胞在感染过程中所经历的氧可用性、铁限制和膜扰动的变化表现出失调的反应。arcA突变体对阳离子抗菌肽多粘菌素B的遗传反应支持了arcA作为膜损伤激活剂的扩展作用。通过对羰基氰化物-间氯苯腙（CCCP）质子动力解耦的响应，将ArcA功能与电子传递链活性联系起来。在CCCP处理后，arcA突变体和野生型细胞之间乳酸、醋酸和乳酸脱氢酶活性的差异支持了arcA介导的独立于氧可用性的发酵转变。这项研究强调了ArcA在菌血症中的半保守作用，并将感染表型整合到一个基于呼吸活动的综合模型中。血液感染会危及生命，并可能导致败血症。革兰氏阴性菌引起很大一部分血液感染，这也被称为菌血症。我们工作的长期目标是了解这些细菌如何在菌血症期间建立和维持感染。我们之前已经确定了促进细菌发酵的转录因子ArcA，可能是这种环境下细菌生长和存活的一个因素。在这里，我们研究了革兰氏阴性种的ArcA，包括弗氏柠檬酸杆菌、肺炎克雷伯菌和粘质沙雷菌。我们的发现有助于确定这些细菌如何感知环境，利用营养物质，并在对抗宿主免疫系统的同时产生能量。这一信息对于开发更好的感染模型，为未来的治疗开发提供信息至关重要。
Gram-negative facultative anaerobes often cause bacteremia, a systemic infection associated with severe clinical outcomes. ArcAB, a two-component regulatory system that represses aerobic respiration, is a key mediator of metabolic adaptation for such bacteria. Using targeted mutational analysis informed by global genetic screens, we identified the arcA gene as promoting fitness of Citrobacter freundii, Klebsiella pneumoniae, and Serratia marcescens but not Escherichia coli in a murine model of bacteremia. arcA mutants exhibit a dysregulated response to changes in oxygen availability, iron limitation, and membrane perturbations, which bacterial cells experience during infection. The genetic response of the arcA mutants to the cationic antimicrobial peptide polymyxin B supports an expanded role for ArcA as an activator in response to membrane damage. ArcA function is linked to electron transport chain activity based on its response to proton motive force uncoupling by carbonylcyanide-m-chlorophenylhydrazone (CCCP). Differences in lactate, acetate, and lactate dehydrogenase activity between arcA mutant and wild-type cells following CCCP treatment support an ArcA-mediated shift to fermentation independent of oxygen availability. This study highlights the semi-conserved role of ArcA during bacteremia and consolidates infection phenotypes into a comprehensive model based on respiratory activity. Infections of the bloodstream are life-threatening and can result in sepsis. Gram-negative bacteria cause a significant portion of bloodstream infections, which is also referred to as bacteremia. The long-term goal of our work is to understand how such bacteria establish and maintain infection during bacteremia. We have previously identified the transcription factor ArcA, which promotes fermentation in bacteria, as a likely contributor to the growth and survival of bacteria in this environment. Here, we study ArcA in the Gram-negative species Citrobacter freundii, Klebsiella pneumoniae, and Serratia marcescens. Our findings aid in determining how these bacteria sense their environment, utilize nutrients, and generate energy while countering the host immune system. This information is critical for developing better models of infection to inform future therapeutic development.
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DOI：
10.1093/bioinformatics/btr064
发表时间：
2011-04-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Grant CE;Bailey TL;Noble WS
通讯作者：
Noble WS
影响因子：
4.4
作者：
Gao H;Wang X;Yang ZK;Palzkill T;Zhou J
通讯作者：
Zhou J
影响因子：
6.4
作者：
Anderson MT;Brown AN;Pirani A;Smith SN;Photenhauer AL;Sun Y;Snitkin ES;Bachman MA;Mobley HLT
通讯作者：
Mobley HLT
影响因子：
5.4
作者：
Alteri CJ;Mobley HL
通讯作者：
Mobley HL
影响因子：
4.6
作者：
Anderson MT;Mitchell LA;Zhao L;Mobley HLT
通讯作者：
Mobley HLT