Nox2 modification of LDL is essential for optimal apolipoprotein B-mediated control of agr type III Staphylococcus aureus quorum-sensing.
Nox2 modification of LDL is essential for optimal apolipoprotein B-mediated control of agr type III Staphylococcus aureus quorum-sensing.
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DOI：
10.1371/journal.ppat.1003166
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发表时间：
2013-02
期刊：
影响因子：
6.7
通讯作者：
Gresham HD
中科院分区：
文献类型：
--
作者：
Hall PR;Elmore BO;Spang CH;Alexander SM;Manifold-Wheeler BC;Castleman MJ;Daly SM;Peterson MM;Sully EK;Femling JK;Otto M;Horswill AR;Timmins GS;Gresham HD
金黄色葡萄球菌含有一个编码在agr操纵子内的自诱导群体感应系统，该系统协调侵袭性感染所需的毒力基因的表达。agr内的等位基因变异产生了四个agr特异性组，agr I-IV，每个组分泌一个不同的自诱导肽信息素（AIP 1 -4），驱动agr信号。由于agr信号介导的表型变化，在这种病原体从粘附定植表型与相当大的组织损伤和侵袭性，我们推测，一个显着的贡献，宿主防御组织损伤和侵入性感染，可以提供先天免疫机制，拮抗agr信号。我们确定了两个宿主防御因子，抑制AIP 1诱导的agrI信号，Nox 2和载脂蛋白B（apoB），是否也有助于先天控制AIP 3诱导的agrIII信号。我们假设apoB和Nox 2对AIP 3的功能不同，AIP 3在氨基酸序列和长度上不同于AIP 1。在这里，我们表明，不像AIP 1，AIP 3是耐直接氧化剂失活的Nox 2特征活性氧。相反，Nox 2对防御agrIII信号传导的贡献是通过氧化LDL。载脂蛋白B在氧化低密度脂蛋白的情况下，而不是低密度脂蛋白，提供了最佳的宿主防御S。通过结合分泌的信号肽AIP 3和阻止介导侵入性感染的agr驱动的毒力因子的表达，抑制金黄色葡萄球菌agr III感染。在oxLDL的情况下，ApoB也结合AIP 1-4，并且oxLDL通过所有四个agr等位基因拮抗agr信号传导。我们的研究结果表明，Nox 2介导的氧化LDL促进apoB的构象变化足以结合和螯合所有四个AIP，证明apoB和Nox 2在宿主防御agr信号的相互依赖性。这些数据揭示了oxLDL在宿主防御S. aureus群体感应信号传导。 金黄色葡萄球菌是人类的常见定植者，但也可引起严重的侵入性感染。S.金黄色葡萄球菌使用基于分泌肽的通讯系统AGR来诱导产生侵入性感染所需的毒力因子。等位基因变异产生了四种agr类型，agr I-IV，并且每种类型分泌不同的自诱导肽（AIP 1 -4），其在氨基酸序列和长度上不同。了解阻止四个agr特异性组（agrI-IV）中的每一个的信号传导的宿主因素可以为预防感染或治疗干预提供机会。我们以前证明，载脂蛋白B（apoB），极低和低密度脂蛋白（VLDL，LDL）的主要结构蛋白，结合到分泌的agr Ⅰ肽，AIP 1，并阻止agr信号。此外，NADPH氧化酶Nox 2产生直接修饰和失活AIP 1的活性氧物质。在这里，我们研究了apoB和Nox 2在防御agrIII信号转导中的作用。我们发现，apoB在氧化LDL，但不是在天然LDL，介导的AIP 3的最佳结合。此外，与AIP 1不同，Nox 2并不直接与AIP 3结合。相反，Nox 2通过氧化LDL来防御agrIII信号传导。此外，我们发现oxLDL结合所有四个AIP和拮抗agr信号的每个agr等位基因在体外。这些结果扩展了我们对宿主防御S. aureus agr信号转导。
Staphylococcus aureus contains an autoinducing quorum-sensing system encoded within the agr operon that coordinates expression of virulence genes required for invasive infection. Allelic variation within agr has generated four agr specific groups, agr I–IV, each of which secretes a distinct autoinducing peptide pheromone (AIP1-4) that drives agr signaling. Because agr signaling mediates a phenotypic change in this pathogen from an adherent colonizing phenotype to one associated with considerable tissue injury and invasiveness, we postulated that a significant contribution to host defense against tissue damaging and invasive infections could be provided by innate immune mechanisms that antagonize agr signaling. We determined whether two host defense factors that inhibit AIP1-induced agrI signaling, Nox2 and apolipoprotein B (apoB), also contribute to innate control of AIP3-induced agrIII signaling. We hypothesized that apoB and Nox2 would function differently against AIP3, which differs from AIP1 in amino acid sequence and length. Here we show that unlike AIP1, AIP3 is resistant to direct oxidant inactivation by Nox2 characteristic ROS. Rather, the contribution of Nox2 to defense against agrIII signaling is through oxidation of LDL. ApoB in the context of oxLDL, and not LDL, provides optimal host defense against S. aureus agrIII infection by binding the secreted signaling peptide, AIP3, and preventing expression of the agr-driven virulence factors which mediate invasive infection. ApoB within the context of oxLDL also binds AIP 1-4 and oxLDL antagonizes agr signaling by all four agr alleles. Our results suggest that Nox2-mediated oxidation of LDL facilitates a conformational change in apoB to one sufficient for binding and sequestration of all four AIPs, demonstrating the interdependence of apoB and Nox2 in host defense against agr signaling. These data reveal a novel role for oxLDL in host defense against S. aureus quorum-sensing signaling. Staphylococcus aureus is a common colonizer of humans but can also cause severe, invasive infection. S. aureus uses a secreted peptide-based communication system, agr, to induce production of virulence factors needed for invasive infection. Allelic variation has generated four agr types, agr I–IV, and each secretes a distinct autoinducing peptide (AIP1-4) that differs in amino acid sequence and length. Understanding host factors that prevent signaling by each of the four agr specific groups (agrI–IV) could provide opportunities for prevention of infection or therapeutic intervention. We previously demonstrated that apolipoprotein B (apoB), the major structural protein of very low and low density lipoproteins (VLDL, LDL), binds to the secreted agrI peptide, AIP1, and prevents agr signaling. In addition, the NADPH oxidase Nox2 produces reactive oxygen species which directly modify and inactive AIP1. Here we examined the role of apoB and Nox2 in defense against agrIII-signaling. We found that apoB in oxidized LDL, but not in native LDL, mediated optimal binding of AIP3. Also, unlike AIP1, Nox2 did not directly inactivate AIP3. Rather Nox2 contributed to defense against agrIII-signaling by oxidizing LDL. Furthermore, we found that oxLDL bound all four AIPs and antagonized agr signaling by each agr allele in vitro. These results expand our understanding of host defense against S. aureus agr signaling.
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