Li Min, Diep Binh An, Villaruz Amer E, Braughton Kevin R, Jiang Xiaofei, DeLeo Frank R, Chambers Henry F, Lu Yuan, Otto Michael
National Institute of Allergy and Infectious Diseases, National Institutes of Health, 903 South 4th Street, Hamilton, MT 59840, MD 20892, USA.
Proc Natl Acad Sci U S A. 2009 Apr 7;106(14):5883-8. doi: 10.1073/pnas.0900743106. Epub 2009 Mar 17.
Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has recently emerged worldwide. The United States, in particular, is experiencing a serious epidemic of CA-MRSA that is almost entirely caused by an extraordinarily infectious strain named USA300. However, the molecular determinants underlying the pathogenic success of CA-MRSA are mostly unknown. To gain insight into the evolution of the exceptional potential of USA300 to cause disease, we compared the phylogeny and virulence of USA300 with that of closely related MRSA clones. We discovered that the sublineage from which USA300 evolved is characterized by a phenotype of high virulence that is clearly distinct from other MRSA strains. Namely, USA300 and its progenitor, USA500, had high virulence in animal infection models and the capacity to evade innate host defense mechanisms. Furthermore, our results indicate that increased virulence in the USA300/USA500 sublineage is attributable to differential expression of core genome-encoded virulence determinants, such as phenol-soluble modulins and alpha-toxin. Notably, the fact that the virulence phenotype of USA300 was already established in its progenitor indicates that acquisition of mobile genetic elements has played a limited role in the evolution of USA300 virulence and points to a possibly different role of those elements. Thus, our results highlight the importance of differential gene expression in the evolution of USA300 virulence. This finding calls for a profound revision of our notion about CA-MRSA pathogenesis at the molecular level and has important implications for design of therapeutics directed against CA-MRSA.
社区获得性耐甲氧西林金黄色葡萄球菌（CA-MRSA）最近在全球范围内出现。特别是美国，正经历一场严重的CA-MRSA疫情，几乎完全由一种名为USA300的极具传染性的菌株引起。然而，CA-MRSA致病成功的分子决定因素大多未知。为了深入了解USA300导致疾病的特殊潜力的演变，我们将USA300的系统发育和毒力与密切相关的MRSA克隆进行了比较。我们发现USA300进化而来的亚系具有高毒力表型，这与其他MRSA菌株明显不同。也就是说，USA300及其祖先USA500在动物感染模型中具有高毒力，并且有能力逃避宿主的固有防御机制。此外，我们的结果表明，USA300/USA500亚系中毒力增加归因于核心基因组编码的毒力决定因素的差异表达，如酚溶性调节蛋白和α毒素。值得注意的是，USA300的毒力表型在其祖先中就已确立，这一事实表明移动遗传元件的获得在USA300毒力的进化中作用有限，并指出这些元件可能具有不同的作用。因此，我们的结果突出了差异基因表达在USA300毒力进化中的重要性。这一发现要求我们在分子水平上对CA-MRSA发病机制的观念进行深刻修正，并对针对CA-MRSA的治疗方法设计具有重要意义。
