Staphylococcus aureus can cause wide range of infections from simple soft skin infections to severe endocarditis, bacteremia, osteomyelitis and implant associated bone infections (IABI). The focus of the present investigation was to study virulence properties of S. aureus isolates from acute and chronic IABI by means of their in vivo lethality, in vitro osteoblasts invasion, biofilm formation and subsequently whole genome comparison between high and low virulent strains. Application of insect infection model Galleria mellonella revealed high, intermediate and low virulence phenotypes of these clinical isolates, which showed good correlation with osteoblast invasion and biofilm formation assays. Comparative genomics of selected high (EDCC 5458) and low (EDCC 5464) virulent strains enabled the identification of molecular factors responsible for the development of acute and chronic IABI. Accordingly, the low virulent strain EDCC 5464 harbored point mutations resulting in frame shift mutations in agrC (histidine kinase in agr system), graS (histidine kinase in graSR, a two component system) and efeB (peroxidase in efeOBU operon, an iron acquisition system) genes. Additionally, we found a mobile element (present 11 copies in EDCC 5464) inserted at the end of β-hemolysin (hlb) and sarU genes, which are involved in the pathogenesis and regulation of virulence gene expression in coordination with quorum sensing system. All these results are in good support with the low virulence behavior of EDCC 5464. From the previous literature, it is well known that agr defective S. aureus clinical strains are isolated from the chronic infections. Similarly, low virulent EDCC 5464 was isolated from chronic implant-associated bone infections infection whereas EDCC 5458 was obtained from acute implant-associated bone infections. Laboratory based in vitro and in vivo results and insights from comparative genomic analysis could be correlated with the clinical conclusion of IABIs and allows evidence-based treatment strategies based on the pathogenesis of the strain to cure life devastating implant-associated infections.

中文翻译：

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高毒力和低毒力金黄色葡萄球菌分离株诱导植入物相关骨感染的全基因组比较。

金黄色葡萄球菌可引起多种感染，从简单的软性皮肤感染到严重的心内膜炎，菌血症，骨髓炎和植入物相关的骨感染（IABI）。本研究的重点是通过其体内致死率，体外成骨细胞入侵，生物膜形成以及随后在高毒力和低毒力菌株之间进行全基因组比较来研究来自急性和慢性IABI的金黄色葡萄球菌分离物的毒力特性。昆虫感染模型的应用梅洛埃勒菌显示出这些临床分离株的高，中和低毒力表型，与成骨细胞侵袭和生物膜形成测定具有良好的相关性。选定的高毒力菌株（EDCC 5458）和低毒力菌株（EDCC 5464）的比较基因组学能够鉴定导致急性和慢性IABI发生的分子因素。因此，低毒力菌株EDCC 5464带有点突变，导致agrC（agr系统中的组氨酸激酶），graS（graSR中的组氨酸激酶，两组分系统）和efeB（efeOBU操纵子中的过氧化物酶，铁捕获系统）发生移码突变。 ）基因。此外，我们发现在β-溶血素（hlb）和sarU基因的末端插入了一个可移动元件（在EDCC 5464中存在11个拷贝），它们与群体感应系统协同作用，参与了毒力基因表达的发病机理和调控。所有这些结果都为EDCC 5464的低毒行为提供了良好的支持。根据以前的文献，众所周知，从慢性感染中分离出农业缺陷型金黄色葡萄球菌临床菌株。类似地，从慢性植入物相关的骨感染感染中分离出低毒性的EDCC 5464，而从急性植入物相关的骨感染中获得了EDCC 5458。基于实验室的体外和体内结果以及来自比较基因组分析的见解可以与IABI的临床结论相关联，并允许基于基于菌株发病机理的循证治疗策略来治愈破坏性生命的植入物相关感染。