共生表葡菌通过抑制金葡菌SaeRS-Hla调控通路降低其毒力的机制

共生凝固酶阴性葡萄球菌（CoNS）对维持皮肤黏膜正常生理功能、抑制病原菌定植感染发挥重要作用。CoNS可通过分泌抗菌分子、刺激宿主分泌抗菌肽等杀伤病原菌。申请人近期发现上呼吸道共生表葡菌还可抑制金葡菌溶血活性而不影响其生长，进一步分析提示共生表葡菌分泌上清通过抑制金葡菌SaeRS调控系统降低溶血素Hla的表达。由此提出科学假设：共生表葡菌分泌信号分子，通过直接或间接途径抑制金葡菌SaeRS-Hla通路，降低金葡菌感染宿主能力。但共生表葡菌产生何种信号分子以及如何发挥对SaeRS-Hla通路的调控作用还有待明确。申请人接下去拟采取转座子插入突变文库筛选、转录组学和蛋白功能分析等研究方法，解析共生表葡菌特定信号分子的结构功能及对金葡菌SaeRS-Hla通路的调控机制，细胞和动物感染模型的建立进一步明确这种调节关系对金葡菌毒力的影响。研究结果为以人体共生菌作为新型生物制剂研发提供理论依据和靶点。

The commensal coagulase-negative Staphylococcus (CoNS) play an important role in maintaining the normal physiological function of skin and mucosa and protecting from the colonization and infection of pathogenic bacteria. CoNS kill the pathogenic bacteria by secreting antimicrobial molecules, or stimulating the secretion of antibacterial peptides from the host cells. We observed that the commensal S. epidermidis inhibit the hemolysis activity but not the growth of S. aureus recently. Further research showed that the commensal S. epidermidis decrease the expression of Hla (α-toxin) of S. aureus by inhibiting SaeRS regulatory system. Therefore, we put forward the following scientific hypothesis: The specific signal molecule, produced from the commensal S. epidermidis, can decrease the pathogenicity of S. aureus by inhibiting the SaeRS-Hla regulatory pathway directly or indirectly. But we did not clarify the specific signal molecule produced by the commensal S. epidermidis and the exact mechanism on how the signal molecule regulates the SaeRS-Hla regulatory pathway. In order to analyze the structure and function of the specific signal molecule produced by S. epidermidis, and clarify the molecular mechanism on how the signal molecular regulates S. aureus SaeRS-Hla pathway, we will use different research methods including screening of transposon mutant library, the transcriptomic assay, the analysis of protein function, etc. The cellular and animal infection model will be further adopted to confirm that the regulatory relation affects the virulence of S. aureus. Our research will provide theoretical basis and target for the research and development of new biological agents.