Role of the ESAT-6 secretion system in virulence of the emerging community-associated Staphylococcus aureus lineage ST398

Yanan Wang,Lei He,Michael Otto,Fan Zhou,Min Li,Tianming Li,Jingyuan Fang,Kaiwen Yu,Juanxiu Qin,Xiaoyun Liu,Yingxin Dai,Mo Hu,Bing Zheng,Qian Liu

doi:10.1038/srep25163

Abstract

Novel Staphylococcus aureus clones continue to emerge that cause infections in otherwise healthy people. One example is the sequence type (ST) 398 lineage, which we show here is increasing in importance as a significant cause of community-associated (CA) human infections in China. We have a profound lack of understanding about what determines the considerable virulence potential of such newly emerging clones. Information about the contribution to virulence of the more recently discovered ESAT-6 secretion system (ESS) has remained particularly scarce. The Chinese ST398 isolates exhibited significantly increased expression of ESS genes as compared to predominant hospital-associated clones, which we found is likely due to increased expression of the accessory gene regulator (Agr) system and control of ESS by Agr. Importantly, deletion of essB in ST398 resulted in significantly reduced resistance to neutrophil killing and decreased virulence in murine skin and blood infection models. Our results demonstrate a key function of ESS in promoting virulence and mechanisms of resistance to innate host defense in an important emerging CA-S. aureus lineage. They suggest that ESS has a so far underestimated role in promoting aggressive virulence and epidemiological success of S. aureus.

Highlights

Staphylococcus aureus is an important pathogen that causes a variety of infections, ranging from localized skin and soft-tissue infections (SSTIs) to life-threatening severe infections such as necrotizing pneumonia or sepsis[1]
The lukSF genes encoding the Panton-Valentine leukocidin (PVL), a leukocidin often epidemiologically associated with CA-methicillin-resistant S. aureus (MRSA) infections[17], were present in only 27.5% of community-associated S. aureus (CA-SA) ST398 isolates from adults and absent from pediatric isolates
CA-SA infections are commonly caused by clones that are entirely different from those encountered in hospitals[6]

Summary

Introduction

Staphylococcus aureus is an important pathogen that causes a variety of infections, ranging from localized skin and soft-tissue infections (SSTIs) to life-threatening severe infections such as necrotizing pneumonia or sepsis[1]. The considerable morbidity and mortality that is due to community-associated infections, caused by both methicillin-resistant and methicillin-sensitive S. aureus isolates, is increasing on a worldwide scale[2,4,5,6]. The molecular processes underlying the capacity of CA-SA ST398 to infect healthy individuals and spread sustainably in the population are poorly understood, but recent results obtained with ST398 isolates from Brazil that caused fatal pneumonia indicate an important role of Agr-controlled toxins, in particular α -toxin, in ST398 virulence[12]. The mechanistic function in pathogenesis of secreted ESS substrates is poorly understood, but results from a recent study indicate a role of EsxA and EsxB in the modulation of apoptosis and release of ingested S. aureus from epithelial cells[16]. By construction and analysis of an essB deletion mutant in ST398, we demonstrate a significant role of ESS in acute ST398 infection, which our results indicate may be due to a previously unrecognized role of ESS in the evasion of destruction by human neutrophils

Methods

Results

Conclusion