Induction of group A Streptococcus virulence by a human antimicrobial peptide
Induction of group A Streptococcus virulence by a human antimicrobial peptide
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DOI：
10.1073/pnas.0803815105
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发表时间：
2008-10-28
影响因子：
11.1
通讯作者：
Wessels, Michael R.
中科院分区：
文献类型：
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作者：
Gryllos, Ioannis;Tran-Winkler, Hien J.;Wessels, Michael R.
A组链球菌（化脓性链球菌或GAS）从链球菌咽喉痛或侵袭性（“食肉”）感染的个体中新鲜分离，通常在原代培养时生长为粘液样菌落，但在实验室传代后失去这种菌落外观。粘液样表型是由于大量产生的透明质酸荚膜多糖，一个关键的毒力决定因素与严重的GAS感染。这些观察结果表明，来自人类宿主的信号在感染期间触发胶囊和可能的其他毒力因子的产生增加。在这里，我们表明，亚抑制浓度的人类抗菌cathelicidin肽LL-37刺激表达的GAS胶囊合成操纵子（hasABC）。上调由CsrRS 2-组分调节系统介导：它需要功能性CsrS传感器蛋白，并且可以通过增加的细胞外Mg 2+（CsrS的另一种鉴定的环境信号）来拮抗。其他CsrRS调节的毒力基因的上调也很明显，包括IL-8蛋白酶PrtS/ScpC和整合素样/IgG蛋白酶Mac/IdeS，这些发现表明这种抗微生物免疫效应肽引起了协调的GAS毒力应答。通过CsrRS的LL-37信号传导导致GAS对人白细胞的调理吞噬杀伤的抗性显著增加，这是增强的GAS毒力的体外测量，与抗吞噬荚膜多糖和Mac/IdeS的表达增加一致。我们提出，人cathelicidin LL-37具有刺激CsrRS调节的毒力基因表达的矛盾作用，从而增强感染期间GAS的致病性。GAS感知和响应LL-37的能力可以至少部分解释人类对链球菌感染的独特易感性。
Group A streptococci (Streptococcus pyogenes or GAS) freshly isolated from individuals with streptococcal sore throat or invasive ("flesh-eating") infection often grow as mucoid colonies on primary culture but lose this colony appearance after laboratory passage. The mucoid phenotype is due to abundant production of the hyaluronic acid capsular polysaccharide, a key virulence determinant associated with severe GAS infections. These observations suggest that signal(s) from the human host trigger increased production of capsule and perhaps other virulence factors during infection. Here we show that subinhibitory concentrations of the human antimicrobial cathelicidin peptide LL-37 stimulate expression of the GAS capsule synthesis operon (hasABC). Up-regulation is mediated by the CsrRS 2-component regulatory system: it requires a functional CsrS sensor protein and can be antagonized by increased extracellular Mg2+, the other identified environmental signal for CsrS. Up-regulation was also evident for other CsrRS-regulated virulence genes, including the IL-8 protease PrtS/ScpC and the integrin-like/IgG protease Mac/IdeS, findings that suggest a coordinated GAS virulence response elicited by this antimicrobial immune effector peptide. LL-37 signaling through CsrRS led to a marked increase in GAS resistance to opsonophagocytic killing by human leukocytes, an in vitro measure of enhanced GAS virulence, consistent with increased expression of the antiphagocytic capsular polysaccharide and Mac/IdeS. We propose that the human cathelicidin LL-37 has the paradoxical effect of stimulating CsrRS-regulated virulence gene expression, thereby enhancing GAS pathogenicity during infection. The ability of GAS to sense and respond to LL-37 may explain, at least in part, the unique susceptibility of the human species to streptococcal infection.