Department of Laboratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University, No. 160 Pujian Road, Shanghai, 200127, China.
Ministry of Education Key Laboratory of Contemporary Anthropology and Center for Evolutionary Biology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, No. 2005 Songhu Road, Shanghai, 200438, China.
Genome Med. 2018 Jan 29;10(1):5. doi: 10.1186/s13073-018-0514-9.
Severe infections with highly virulent community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) are a global problem. However, the molecular events defining the evolution of CA-MRSA are still poorly understood. MRSA of sequence type (ST) 398 is known to frequently infect livestock, while ST398 isolates infecting humans are commonly methicillin-susceptible or represent MRSA originating from livestock-associated (LA)-MRSA.
We used whole genome sequencing of newly detected CA-MRSA ST398 isolates, in comparison to geographically matched LA-MRSA and methicillin-sensitive ST398, to determine their evolutionary history. Furthermore, we used phenotypic analyses including animal infection models to gain insight into the evolution of virulence in these CA-MRSA isolates. Finally, we determined methicillin resistance and expression of the methicillin resistance-conferring gene mecA and its penicillin-binding protein product, PBP2a, in a large series of CA-MRSA strains of divergent STs.
We report several cases of severe and fatal infections due to ST398 CA-MRSA. The responsible isolates showed the typical genetic characteristics reported for human-adapted methicillin-sensitive ST398. Whole genome sequencing demonstrated that they evolved from human-adapted, methicillin-susceptible clones on several different occasions. Importantly, the isolates had not undergone consistent genetic alterations or changes in virulence as compared to their methicillin-susceptible predecessors. Finally, we observed dramatically and consistently lower methicillin resistance and expression of the resistance gene mecA, as compared to hospital-associated MRSA strains, in a diverse selection of CA-MRSA strains.
Our study presents evidence for the development of highly virulent human-adapted ST398 CA-MRSA isolates from methicillin-susceptible predecessors. Notably, our investigation indicates that, in contrast to widespread notions, the development of CA-MRSA is not necessarily associated with the acquisition of specific virulence genes or other virulence-increasing changes. Rather, our findings emphasize the importance of the CA-MRSA-characteristic staphylococcal cassette chromosome mec types, which provide only low-level methicillin resistance, for that process. Our findings are of particular importance for the diagnosis of CA-MRSA, inasmuch as they indicate that the presence of specific virulence genes cannot generally be used for that purpose.
高度毒力的社区获得性耐甲氧西林金黄色葡萄球菌（CA-MRSA）引起的严重感染是一个全球性问题。然而，定义 CA-MRSA 进化的分子事件仍知之甚少。序列型（ST）398 的耐甲氧西林金黄色葡萄球菌已知经常感染家畜，而感染人类的 ST398 分离株通常对甲氧西林敏感，或代表来自家畜相关（LA）-MRSA 的 MRSA。
我们使用新发现的 CA-MRSA ST398 分离株的全基因组测序，与地理匹配的 LA-MRSA 和甲氧西林敏感的 ST398 进行比较，以确定其进化史。此外，我们使用表型分析，包括动物感染模型，深入了解这些 CA-MRSA 分离株中毒力的进化。最后，我们在一系列不同 ST 的 CA-MRSA 菌株中确定了甲氧西林耐药性和耐药基因 mecA 及其青霉素结合蛋白产物 PBP2a 的表达。
我们报告了几起因 ST398 CA-MRSA 引起的严重和致命感染病例。负责的分离株表现出与人类适应的甲氧西林敏感 ST398 报道的典型遗传特征。全基因组测序表明，它们是由多次人类适应的甲氧西林敏感克隆进化而来。重要的是，与它们的甲氧西林敏感前体相比，分离株没有经历一致的遗传改变或毒力改变。最后，我们观察到与医院相关的 MRSA 菌株相比，在多种 CA-MRSA 菌株中，甲氧西林耐药性和耐药基因 mecA 的表达明显且一致地降低。
我们的研究提供了证据，证明高度毒力的人类适应 ST398 CA-MRSA 分离株是由甲氧西林敏感的前体发展而来的。值得注意的是，我们的研究表明，与普遍的观点相反，CA-MRSA 的发展不一定与特定毒力基因或其他增加毒力的变化的获得有关。相反，我们的发现强调了 CA-MRSA 特征性葡萄球菌盒染色体 mec 类型的重要性，这些类型仅提供低水平的甲氧西林耐药性，这对于该过程至关重要。我们的研究结果对于 CA-MRSA 的诊断尤为重要，因为它们表明不能普遍使用特定毒力基因来进行诊断。
