Department of Pharmaceutical Sciences, University of New Mexico College of Pharmacy, Albuquerque, New Mexico, USA.
PLoS Pathog. 2013 Feb;9(2):e1003166. doi: 10.1371/journal.ppat.1003166. Epub 2013 Feb 14.
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.
金黄色葡萄球菌含有一个自动诱导的群体感应系统，该系统编码在 agr 操纵子中，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 特定组，agr I-IV，每个组都分泌一种独特的自动诱导肽信号分子 (AIP1-4)，驱动 agr 信号。由于 agr 信号介导了这种病原体从粘附定植表型到与严重组织损伤和侵袭性相关的表型的变化，我们假设拮抗 agr 信号的先天免疫机制可以为宿主防御组织损伤和侵袭性感染提供重要贡献。我们确定了两种抑制 AIP1 诱导的 agrI 信号的宿主防御因子，Nox2 和载脂蛋白 B (apoB)，是否也有助于先天控制 AIP3 诱导的 agrIII 信号。我们假设 apoB 和 Nox2 将针对 AIP3 发挥不同的作用，因为 AIP3 在氨基酸序列和长度上与 AIP1 不同。在这里，我们表明与 AIP1 不同，AIP3 不易受到 Nox2 特征性 ROS 直接氧化失活。相反，Nox2 对防御 agrIII 信号的贡献是通过氧化 LDL 实现的。oxLDL 中的 apoB，而不是 LDL，通过结合分泌的信号肽 AIP3 并防止 agr 驱动的毒力因子表达，从而提供对金黄色葡萄球菌 agrIII 感染的最佳宿主防御，这些毒力因子介导侵袭性感染。oxLDL 中的 apoB 也结合 AIP1-4，并且 oxLDL 通过所有四个 agr 等位基因拮抗 agr 信号。我们的结果表明，Nox2 介导的 LDL 氧化促进 apoB 发生构象变化，使其足以结合和隔离所有四种 AIPs，证明了 apoB 和 Nox2 在宿主防御 agr 信号中的相互依存关系。这些数据揭示了 oxLDL 在宿主防御金黄色葡萄球菌群体感应信号中的新作用。
