Department of Immunology and Infectious Diseases, Montana State University, Bozeman, Montana, United States of America.
PLoS Pathog. 2012;8(4):e1002624. doi: 10.1371/journal.ppat.1002624. Epub 2012 Apr 5.
The innate immune system is the first line of host defense against invading organisms. Thus, pathogens have developed virulence mechanisms to evade the innate immune system. Here, we report a novel means for inhibition of neutrophil recruitment by Group A Streptococcus (GAS). Deletion of the secreted esterase gene (designated sse) in M1T1 GAS strains with (MGAS5005) and without (MGAS2221) a null covS mutation enhances neutrophil ingress to infection sites in the skin of mice. In trans expression of SsE in MGAS2221 reduces neutrophil recruitment and enhances skin invasion. The sse deletion mutant of MGAS5005 (Δsse(MGAS5005)) is more efficiently cleared from skin than the parent strain. SsE hydrolyzes the sn-2 ester bond of platelet-activating factor (PAF), converting biologically active PAF into inactive lyso-PAF. K(M) and k(cat) of SsE for hydrolysis of 2-thio-PAF were similar to those of the human plasma PAF acetylhydrolase. Treatment of PAF with SsE abolishes the capacity of PAF to induce activation and chemotaxis of human neutrophils. More importantly, PAF receptor-deficient mice significantly reduce neutrophil infiltration to the site of Δsse(MGAS5005) infection. These findings identify the first secreted PAF acetylhydrolase of bacterial pathogens and support a novel GAS evasion mechanism that reduces phagocyte recruitment to sites of infection by inactivating PAF, providing a new paradigm for bacterial evasion of neutrophil responses.
先天免疫系统是宿主防御入侵生物的第一道防线。因此，病原体已经开发出了毒力机制来逃避先天免疫系统。在这里，我们报告了一种新型的抑制 A 组链球菌（GAS）招募中性粒细胞的方法。M1T1 GAS 菌株（MGAS5005 和 MGAS2221）中分泌酯酶基因（sse）缺失增强了中性粒细胞向小鼠皮肤感染部位的浸润。在 MGAS2221 中转基因表达 SsE 减少了中性粒细胞的募集并增强了皮肤入侵。MGAS5005 的 sse 缺失突变体（Δsse（MGAS5005））比亲本菌株更有效地从皮肤中清除。SsE 水解血小板激活因子（PAF）的 sn-2 酯键，将生物活性的 PAF 转化为无活性的溶血 PAF。SsE 水解 2-硫代-PAF 的 K（M）和 k（cat）与人类血浆 PAF 乙酰水解酶相似。用 SsE 处理 PAF 会消除 PAF 诱导人中性粒细胞激活和趋化的能力。更重要的是，PAF 受体缺陷型小鼠显著减少了对Δsse（MGAS5005）感染部位中性粒细胞的浸润。这些发现确定了细菌病原体的第一个分泌性 PAF 乙酰水解酶，并支持一种新的 GAS 逃避机制，该机制通过使 PAF 失活来减少吞噬细胞对感染部位的募集，为细菌逃避中性粒细胞反应提供了新的范例。
