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. The bacteria known as Streptococcus pyogenes and Staphylococcus aureus are important human pathogens that cause a variety of diseases, including strep throat, toxic shock syndrome, and/or skin infection. These bacteria require iron for growth. However, free iron is quite scarce in human tissues, and bacteria have developed several approaches for acquiring the iron needed for their growth. The majority of iron in mammals is heme, which is present in some proteins. For example, one of the most common heme-containing proteins in humans is hemoglobin from red blood cells. To obtain iron, bacteria have developed approaches for acquiring heme from host proteins and internalizing it, which is degraded to provide bacterial cells with the needed iron. The heme acquisition machineries in Streptococcus pyogenes and Staphylococcus aureus consist of surface proteins and a transmembrane transporter. However, the specific pathway and mechanism of the heme acquisition process are not well understood. The roles of the surface proteins of Streptococcus pyogenes and Staphylococcus aureus in the heme acquisition process by these bacteria have been studied. The surface protein Shr of Streptococcus pyogenes binds heme, and the other surface protein Shp relays heme from Shr to the transmembrane transporter. It also has been demonstrated that the surface protein IsdA of Staphylococcus aureus directly and rapidly transfers its heme to the other surface protein IsdC. These studies suggest that these surface proteins relay heme from host proteins to the transporter for subsequent internalization. These results greatly enhance our understanding of the mechanisms of heme acquisition in Streptococcus pyogenes and Staphylococcus aureus and may serve as a general model for heme acquisition in many other Gram-positive pathogens. Understanding of how these bacteria utilize heme to survive in humans may provide clues on how to block the heme transport for developing new therapeutics to combat these harmful pathogens.