Membrane damage elicits an immunomodulatory program in Staphylococcus aureus.
Membrane damage elicits an immunomodulatory program in Staphylococcus aureus.
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DOI：
10.1371/journal.ppat.1000802
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发表时间：
2010-03-12
期刊：
影响因子：
6.7
通讯作者：
Skaar EP
中科院分区：
文献类型：
--
作者：
Attia AS;Benson MA;Stauff DL;Torres VJ;Skaar EP
金黄色葡萄球菌HrtAB系统是由ATP酶（HrtA）和通透酶（HrtB）组成的氯化血红素调节的ABC转运蛋白，其保护S.金黄色葡萄球菌对氯化血红素毒性的影响。S.缺乏hrtA的金黄色葡萄球菌菌株表现出肝特异性高毒力，并且在氯化血红素暴露时过表达和分泌免疫调节因子，所述免疫调节因子干扰中性粒细胞向感染部位的募集。已经提出缺乏hrtAB的菌株中血红素积累是触发S.金黄色葡萄球菌来阐述这种抗中性粒细胞反应。然而，我们在这里报告说，S。表达无催化活性的HrtA的金黄色葡萄球菌菌株不阐述相同的分泌蛋白质谱。这一结果表明，HrtA的物理缺乏是负责增加免疫调节因子的表达，而HrtA的ATP酶活性的缺陷不有助于这一过程。此外，缺乏hrtA的菌株中的HrtB表达降低了与渗透酶功能失调一致的膜完整性。基于这些研究结果，我们提出了一个模型，其中氯化血红素介导的HrtB的过度表达的HrtA的情况下，通过孔的形成损害葡萄球菌膜。S.金黄色葡萄球菌感觉到这种膜损伤，触发免疫调节因子的表达增加。为了支持这一模型，野生型S.用抗葡萄球菌通道形成肽处理的金黄色葡萄球菌产生模拟用氯化血红素处理ΔhrtA的效果的分泌蛋白质谱。这些结果表明S.金黄色葡萄球菌感知膜损伤，并详细阐述了一个基因表达程序，该程序保护生物体免受宿主先天免疫反应的影响。 金黄色葡萄球菌几乎感染人体内的每一个组织，利用一系列毒力因子来对抗宿主防御。这些毒力因子的表达是一个严格调控的过程，然而，S。金黄色葡萄球菌感染期间仍然难以捉摸。据推测，血红素毒性是由S。金黄色葡萄球菌。这一假说是基于S.由于ATP酶HrtA失活而不能减轻血红素毒性的金黄色葡萄球菌突变体引起干扰中性粒细胞募集到感染部位的免疫调节程序。在这种情况下，S。金黄色葡萄球菌hrtA突变体表现出肝特异性的超强毒力。在此，我们提供了另一种模型来解释的超毒力表型的S。金黄色葡萄球菌ΔhrtA.我们证明，而不是积累的血红素毒性所观察到的免疫调节程序的触发器，由HrtB通透酶引起的孔形成失调触发抗中性粒细胞反应。为了支持该模型，在野生型S.金黄色葡萄球菌或暴露的S.金黄色葡萄球菌对通道形成抗微生物肽的作用诱导类似的免疫调节程序。我们的工作证明S.金黄色葡萄球菌感知膜损伤并诱导免疫调节回路，该免疫调节回路帮助病原体逃避免疫介导的清除。
The Staphylococcus aureus HrtAB system is a hemin-regulated ABC transporter composed of an ATPase (HrtA) and a permease (HrtB) that protect S. aureus against hemin toxicity. S. aureus strains lacking hrtA exhibit liver-specific hyper-virulence and upon hemin exposure over-express and secrete immunomodulatory factors that interfere with neutrophil recruitment to the site of infection. It has been proposed that heme accumulation in strains lacking hrtAB is the signal which triggers S. aureus to elaborate this anti-neutrophil response. However, we report here that S. aureus strains expressing catalytically inactive HrtA do not elaborate the same secreted protein profile. This result indicates that the physical absence of HrtA is responsible for the increased expression of immunomodulatory factors, whereas deficiencies in the ATPase activity of HrtA do not contribute to this process. Furthermore, HrtB expression in strains lacking hrtA decreases membrane integrity consistent with dysregulated permease function. Based on these findings, we propose a model whereby hemin-mediated over-expression of HrtB in the absence of HrtA damages the staphylococcal membrane through pore formation. In turn, S. aureus senses this membrane damage, triggering the increased expression of immunomodulatory factors. In support of this model, wildtype S. aureus treated with anti-staphylococcal channel-forming peptides produce a secreted protein profile that mimics the effect of treating ΔhrtA with hemin. These results suggest that S. aureus senses membrane damage and elaborates a gene expression program that protects the organism from the innate immune response of the host. Staphylococcus aureus infects almost every tissue within the human body utilizing a range of virulence factors to combat host defenses. The expression of these virulence factors is a tightly regulated process; however, the signals sensed by S. aureus during infection remain elusive. It has been hypothesized that heme toxicity is a signal sensed by S. aureus during infection. This hypothesis is based on the observation that S. aureus mutants which are incapable of relieving heme-toxicity due to inactivation of the ATPase HrtA elicit an immunomodulatory program that interferes with neutrophil recruitment to the site of infection. In keeping with this, S. aureus hrtA mutants exhibit liver-specific hypervirulence. Herein, we provide evidence for an alternative model to explain the hypervirulent phenotype of S. aureus ΔhrtA. We demonstrate that instead of accumulation of heme toxicity being the trigger for the observed immunomodulatory program, dysregulated pore formation caused by the HrtB permease triggers the anti-neutrophil response. In support of this model, over-expression of HrtB in wildtype S. aureus or exposing S. aureus to channel-forming antimicrobial peptides induces a similar immunomodulatory program. Our work provides evidence that S. aureus senses membrane damage and induces an immunomodulatory circuit that helps the pathogen evade immune-mediated clearance.
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DOI：
10.1099/00221287-6-1-2-95
发表时间：
1952-01-01
期刊：
JOURNAL OF GENERAL MICROBIOLOGY
影响因子：
--
作者：
DUTHIE, ES;LORENZ, LL
通讯作者：
LORENZ, LL
影响因子：
6.7
作者：
Friedman DB;Stauff DL;Pishchany G;Whitwell CW;Torres VJ;Skaar EP
通讯作者：
Skaar EP
影响因子：
4.8
作者：
Harder, J;Bartels, J;Schröder, JM
通讯作者：
Schröder, JM
DOI：
10.1128/cdli.10.1.161-166.2003
发表时间：
2003-01-01
期刊：
CLINICAL AND DIAGNOSTIC LABORATORY IMMUNOLOGY
影响因子：
--
作者：
Dinulos, JGH;Mentele, L;Darmstadt, GL
通讯作者：
Darmstadt, GL
DOI：
10.1073/pnas.0404728101
发表时间：
2004-08-17
影响因子：
11.1
作者：
Bae, T;Banger, AK;Missiakas, DM
通讯作者：
Missiakas, DM