MT VET COBRE PROJECT 2: METAL UPTAKE AND REGULATION IN STREPTOCOCCUS PYOGENES

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 A组链球菌（GAS）是引起多种疾病的主要人类病原体，包括咽炎、链球菌中毒性休克综合征、坏死性筋膜炎、急性风湿热和肾小球肾炎。金属获取系统是许多细菌病原体的毒力因子和有吸引力的免疫靶点。 GAS含有三种ABC金属获取转运蛋白，即HtsABC、FtsABCD和MtsABC。 本项目的目的是破译的收购过程中的必需金属离子在GAS方面的收购机制，调节，并对发病机制的影响。 我们发现，细胞表面蛋白Shp直接和快速地将其血红素转移到HtsA，并且存在从Shp的轴向配体突变体到HtsA的血红素转移的中间体，这表明了一种意想不到的机制，即同时攻击Shp中的结合血红素的两侧由HtsA。 除了这些发现之外，我们还鉴定了分泌的酯酶Sse，并且用Sse主动和被动免疫保护小鼠免受皮下GAS感染。 这些研究推进了我们对GAS发病机制的理解，并可能确定针对GAS感染的新疫苗和治疗靶点。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Group A Streptococcus (GAS) is a major human pathogen causing a variety of diseases, including pharyngitis, streptococcal toxic shock syndrome, necrotizing fasciitis, acute rheumatic fever, and glomerulonephritis. Metal acquisition systems of many bacterial pathogens are virulence factors and attractive immunotherapeutic targets. GAS contains three ABC metal acquisition transporters, namely, HtsABC, FtsABCD, and MtsABC. The objective of this project is to decipher the acquisition processes of essential metal ions in GAS with respect to the acquisition machinery, regulation, and impacts on pathogenesis. We found that the cell surface protein Shp directly and rapidly transfers its heme to HtsA and that there is an intermediate in the heme transfer from the axial ligand mutants of Shp to HtsA, suggesting an unexpected mechanism of simultaneously attack on both sides of the bound heme in Shp by HtsA. In addition to these findings, we also identified secreted esterase Sse, and active and passive immunizations with Sse protect mice against subcutaneous GAS infection. These studies advance our understanding of GAS pathogenesis and may identify novel vaccine and therapeutic targets against GAS infection.