A Novel ESAT-6 Secretion System-Secreted Protein EsxX of Community-Associated Staphylococcus aureus Lineage ST398 Contributes to Immune Evasion and Virulence.

Yingxin Dai,Yanan Wang,Huiying Lu,Min Li,Qian Liu,Hongwei Meng,Juanxiu Qin,Mo Hu,Qianqian Gao

doi:10.3389/fmicb.2017.00819

Yingxin Dai, Yanan Wang + Show 7 more

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https://doi.org/10.3389/fmicb.2017.00819

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Abstract

The ESAT-6 secretion system (ESS) has been reported to contribute to the virulence and pathogenicity of several Staphylococcus aureus strains such as USA300 and Newman. However, the role of the ESS in community-associated S. aureus (CA-SA) lineage ST398 in China is not well understood. By comparing the ess locus of ST398 with the published S. aureus sequence in the NCBI database, we found one gene in the ess locus encoding a novel WXG superfamily protein that is highly conserved only in ST398. LC-MS/MS and Western blot analysis revealed that this protein is a novel secreted protein controlled by the ST398 ESS, and we named the protein EsxX. Although EsxX was not under the control of the accessory gene regulator like many other virulence factors and had no influence on several phenotypes of ST398, such as growth, hemolysis, and biofilm formation, it showed important impacts on immune evasion and virulence in ST398. An esxX deletion mutant led to significantly reduced resistance to neutrophil killing and decreased virulence in murine skin and blood infection models, indicating its essential contribution to the evasion of innate host defense and virulence to support the pathogenesis of ST398 infections. The function of this novel secreted protein EsxX might help us better understand the role of the ESS in the virulence and epidemic success of the CA-SA lineage ST398.

Highlights

Staphylococcus aureus is an important pathogen that causes a broad range of infections, including the majority of skin and soft tissue infections (SSTIs) and some life-threatening infections such as necrotizing pneumonia and fatal endocarditis (Lowy, 1998; Schijffelen et al, 2010)
One of our studies showed that the prevalence of the community-associated S. aureus (CA-SA) ST398 is increasing in China, and we have reported the contribution of the ESAT-6 secretion system (ESS) to the virulence of the emerging community-associated S. aureus (CASA) lineage for the first time (Wang et al, 2016)
We performed sequence alignment of esxX among clinical S. aureus isolates and strains in the NCBI database and found that it is highly conserved in S. aureus lineage ST398. 61 isolates of S. aureus ST398 derived from infected patients and 15 isolates derived from cattle suffering from mastitis were collected in this study

Summary

Introduction

Staphylococcus aureus is an important pathogen that causes a broad range of infections, including the majority of skin and soft tissue infections (SSTIs) and some life-threatening infections such as necrotizing pneumonia and fatal endocarditis (Lowy, 1998; Schijffelen et al, 2010). Protein EsxX Contributes to Virulence immune responses (Foster, 2009; Edwards and Massey, 2011; Spaan et al, 2013) Those virulence factors require secretion systems to translocate across the membrane. A study indicated that EsxA and EsxB are involved in the modulation of apoptosis and release of ingested S. aureus from epithelial cells (Korea et al, 2014), focusing on the mechanistic function of secreted ESS substrates in pathogenesis. The majority of studies regarding ESS function were performed in USA300 and Newman (Burts et al, 2005, 2008; Anderson et al, 2011, 2013; Kneuper et al, 2014), two epidemic strains of community-associated S. aureus (CASA) in America. There are straindependent differences in the ess locus among a broad range of S. aureus strains of different CC or sequence types, showing unexpected genetic diversity, which indicates that there might be strain-specific substrates and functions (Warne et al, 2016)

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