Vitamin D and the human antimicrobial peptide LL-37 enhance group a streptococcus resistance to killing by human cells.
Vitamin D and the human antimicrobial peptide LL-37 enhance group a streptococcus resistance to killing by human cells.
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DOI：
10.1128/mbio.00394-12
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发表时间：
2012-10-23
期刊：
影响因子：
6.4
通讯作者：
Wessels MR
中科院分区：
文献类型：
--
作者：
Love JF;Tran-Winkler HJ;Wessels MR
A群链球菌（GAS; Streptococcus pyogenes）的CsrRS双组分调控系统对人抗菌肽LL-37的亚抑制浓度有响应。通过CsrRS的LL-37信号导致直接合成毒力因子的基因上调，包括透明质酸胶囊和溶链素O （SLO）。在这里，我们证明了这种反应的结果是增强了GAS对人口咽角质形成细胞、中性粒细胞和巨噬细胞杀伤的抵抗力。ll -37诱导的SLO和透明质酸胶囊的上调显著降低了角质形成细胞对GAS的内化以及中性粒细胞和巨噬细胞的吞噬杀伤。由于维生素D诱导巨噬细胞产生LL-37，我们测试了其对巨噬细胞杀死GAS的作用。与报道的巨噬细胞对其他病原体的功能增强相反，用1α，25-二羟基维生素D3治疗巨噬细胞反而降低了巨噬细胞控制GAS感染的能力。这些观察结果表明，LL-37信号通过CsrRS诱导GAS的毒力表型，其特征是对上皮细胞和吞噬细胞的摄取和杀伤的抵抗力增强。通过诱导巨噬细胞产生LL-37，维生素D可能导致GAS感染的这种矛盾加剧。为什么A群链球菌（GAS）在大多数个体中引起无症状定植或局部喉咙炎症，但很少发展为侵袭性感染，人们仍然知之甚少。人抗微生物肽LL-37作为对GAS感染的先天免疫应答的一部分产生，通过GAS CsrRS双组分调控系统发出信号，上调多种毒力因子的表达。本研究报道了两个csrrs调控的GAS毒力因子——溶链素O和透明质酸胶囊——在ll -37诱导的GAS抵抗人喉咙上皮细胞、中性粒细胞和巨噬细胞的杀伤中起关键作用。维生素D增加巨噬细胞中LL-37的产生，具有增加GAS对巨噬细胞介导的杀伤的抗性的矛盾作用。通过这种方式，人类先天免疫反应可能促进GAS定植向侵袭性感染的转变。
The CsrRS two-component regulatory system of group A Streptococcus (GAS; Streptococcus pyogenes) responds to subinhibitory concentrations of the human antimicrobial peptide LL-37. LL-37 signaling through CsrRS results in upregulation of genes that direct synthesis of virulence factors, including the hyaluronic acid capsule and streptolysin O (SLO). Here, we demonstrate that a consequence of this response is augmented GAS resistance to killing by human oropharyngeal keratinocytes, neutrophils, and macrophages. LL-37-induced upregulation of SLO and hyaluronic acid capsule significantly reduced internalization of GAS by keratinocytes and phagocytic killing by neutrophils and macrophages. Because vitamin D induces LL-37 production by macrophages, we tested its effect on macrophage killing of GAS. In contrast to the reported enhancement of macrophage function in relation to other pathogens, treatment of macrophages with 1α,25-dihydroxy-vitamin D3 paradoxically reduced the ability of macrophages to control GAS infection. These observations demonstrate that LL-37 signals through CsrRS to induce a virulence phenotype in GAS characterized by heightened resistance to ingestion and killing by both epithelial cells and phagocytes. By inducing LL-37 production in macrophages, vitamin D may contribute to this paradoxical exacerbation of GAS infection. It remains poorly understood why group A Streptococcus (GAS) causes asymptomatic colonization or localized throat inflammation in most individuals but rarely progresses to invasive infection. The human antimicrobial peptide LL-37, which is produced as part of the innate immune response to GAS infection, signals through the GAS CsrRS two-component regulatory system to upregulate expression of multiple virulence factors. This study reports that two CsrRS-regulated GAS virulence factors—streptolysin O and the hyaluronic acid capsule—are critical in LL-37-induced resistance of GAS to killing by human throat epithelial cells and by neutrophils and macrophages. Vitamin D, which increases LL-37 production in macrophages, has the paradoxical effect of increasing GAS resistance to macrophage-mediated killing. In this way, the human innate immune response may promote the transition from GAS colonization to invasive infection.