Serotype M3 and M28 Group A Streptococci Have Distinct Capacities to Evade Neutrophil and TNF-α Responses and to Invade Soft Tissues.
Serotype M3 and M28 Group A Streptococci Have Distinct Capacities to Evade Neutrophil and TNF-α Responses and to Invade Soft Tissues.
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DOI：
10.1371/journal.pone.0129417
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Lei B
中科院分区：
文献类型：
--
作者：
Stetzner ZW;Li D;Feng W;Liu M;Liu G;Wiley J;Lei B
在美国和其他工业化国家，A群链球菌（GAS） M3血清型是与严重侵袭性GAS感染（如坏死性筋膜炎）相关的三种最常见的血清型之一。这种关联和侵袭性血清型M3 GAS高毒力的基础尚不完全清楚。本研究对已测序的M3血清型菌株MGAS315和M28血清型菌株MGAS6180进行平行表征，以确定当代M3 GAS是否比M28 GAS具有更高的侵袭软组织的能力。皮下感染时，MGAS315侵袭几乎整个皮肤，抑制中性粒细胞的募集和TNF-α的产生，对小鼠皮下感染具有致死性，而MGAS6180不侵袭皮肤，诱导中性粒细胞的强烈浸润和TNF-α的产生，未能杀死小鼠。与MGAS6180相比，MGAS315存在covS G1370T突变。在MGAS315染色体上用野生型covS替换covS 1370T基因或在MGAS315中反式表达野生型covS，可使covS控制的毒力基因hasA、spyCEP和sse的表达减少10倍。MGAS315冠状病毒失去了广泛侵入皮肤和抑制中性粒细胞募集的能力，毒力减弱，表明冠状病毒G1370T突变对MGAS315的高毒力起关键作用。在功能性CovRS的背景下，MGAS315 covS wt造成的病变仍大于MGAS6180，并且在covS缺失的背景下，MGAS6180 ΔcovS造成的病变仍小于MGAS315 ΔcovS。因此，当代侵袭性M3 GAS比M28 GAS具有更高的逃避中性粒细胞和TNF-α反应和入侵软组织的能力，并且M3 GAS的这种皮肤入侵能力在天然CovRS突变下最大化。这些发现增强了我们对M3气体与坏死性筋膜炎频繁关联的基础的理解。
The M3 Serotype of Group A Streptococcus (GAS) is one of the three most frequent serotypes associated with severe invasive GAS infections, such as necrotizing fasciitis, in the United States and other industrialized countries. The basis for this association and hypervirulence of invasive serotype M3 GAS is not fully understood. In this study, the sequenced serotype M3 strain, MGAS315, and serotype M28 strain, MGAS6180, were characterized in parallel to determine whether contemporary M3 GAS has a higher capacity to invade soft tissues than M28 GAS. In subcutaneous infection, MGAS315 invaded almost the whole skin, inhibited neutrophil recruitment and TNF-α production, and was lethal in subcutaneous infection of mice, whereas MGAS6180 did not invade skin, induced robust neutrophil infiltration and TNF-α production, and failed to kill mice. In contrast to MGAS6180, MGAS315 had covS G1370T mutation. Either replacement of the covS 1370T gene with wild-type covS in MGAS315 chromosome or in trans expression of wild-type covS in MGAS315 reduced expression of CovRS-controlled virulence genes hasA, spyCEP, and sse by >10 fold. MGAS315 covS wt lost the capacity to extensively invade skin and to inhibit neutrophil recruitment and had attenuated virulence, indicating that the covS G1370T mutation critically contribute to the hypervirulence of MGAS315. Under the background of functional CovRS, MGAS315 covS wt still caused greater lesions than MGAS6180, and, consistently under the background of covS deletion, MGAS6180 ΔcovS caused smaller lesions than MGAS315 ΔcovS. Thus, contemporary invasive M3 GAS has a higher capacity to evade neutrophil and TNF-α responses and to invade soft tissue than M28 GAS and that this skin-invading capacity of M3 GAS is maximized by natural CovRS mutations. These findings enhance our understanding of the basis for the frequent association of M3 GAS with necrotizing fasciitis.
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