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

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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.