tarFI2J2L基因簇突变导致医院获得性MRSA壁磷壁酸结构变异影响其适应性的分子机制

医院获得性感染(HAI)是中国MRSA感染主要形式，最主要HA-MRSA流行株是ST239和ST5，申请人前期发现ST239分离率近几年显著下降，体内外研究发现与ST5相比，ST239生长速度和生物被膜形成能力逐年下降，致病力降低。全基因组测序分析发现合成壁磷壁酸（WTA）关键基因簇tarFI2J2L发生突变的ST239分离比率明显增加，推测tarFI2J2L基因簇突变导致WTA结构变异从而降低ST239在医院环境生存及感染的适应性。本课题拟在已获得tarFI2J2L基因突变株基础上，系统分析tarFI2J2L基因簇突变导致WTA结构变异在HA-MRSA定植、感染及可移动基因元件转移中的具体作用和分子机制；阐明促进HA-MRSA流行株tarFI2J2L基因簇发生突变的始动因素，从新的角度诠释MRSA流行病学变化的分子机制，为及时诊断与感控措施的实施以及设计新的抗感染策略提供理论依据和靶点。

Hospital acquired infection (HAI) is the major form of MRSA infection in China. The main HA-MRSA epidemic strains are ST239 and ST5. Previously, the applicants found that the isolation rate of ST239 decreased significantly in recent years. In vivo and in vitro studies showed that the growth rate and biofilm formation of ST239 decreased year by year and ST239 also had lower pathogenicity, compared to ST5. Whole genome sequencing analysis revealed that the isolation rate of ST239 with mutation in tarFI2J2L, a key gene cluster in synthetizing wall phosphoric acid (WTA), increased significantly with each passing year. It was speculated that the mutation of tarFI2J2L gene cluster resulted in structural variation of WTA, which reduced the adaptability of ST239 to hospital environment and infection. Based on the existing clinical strains with tarFI2J2L gene mutants, We propose a multifaceted research approach on the role of tarFI2J2L gene cluster mutant-mediated WTA modulation for the capacities of ST239 HA-MRSA to colonize human epithelia, evade immune recognition, and exchange MGEs with other S. aureus. A panel of defined ST239 HA-MRSA model strains with specific point mutation will also be constructed and the structure-activity relationships of WTA-mediated epithelial cell binding will be elucidated. Moreover, the impact of tarFI2J2L-altered WTA for recognition by human antibodies and complement system will be explored in vitro and in vivo infection models.The initiating factors of tarFI2J2L gene cluster mutation in HA-MRSA epidemic strains will also be clarified. Our project should help to unravel the ecology and evolution of a major human pathogen from a new perspective and create new avenues for the control of HA-MRSA infections.