Heme Synthesis and Acquisition in Staphylococcus aureus

Abstract

The cofactor heme is essential to the growth and virulence of the human pathogen Staphylococcus aureus. S. aureus is capable of synthesizing heme de novo as well as acquiring it from host hemoglobin. The molecular mechanisms by which S. aureus regulates heme synthesis and the genetic requirements for heme synthesis were investigated. The membrane protein HemX was found to regulate heme synthesis by controlling abundance of the first heme biosynthetic enzyme, GtrR. HemX, which is broadly conserved across bacteria, controls GtrR levels post-transcriptionally to prevent excess heme synthesis. Additionally, heme auxotrophy increases GtrR abundance, making GtrR the key regulator of heme synthesis. Genetic dissection of heme synthesis genes suggests that gsaM is only partially required for heme synthesis, while cgoX is required for both aerobic and anaerobic heme synthesis. Turning to heme acquisition, rapid evolution was identified at the host-pathogen interface mediating heme uptake. Primate hemoglobin has been subject to positive selection at the interface of IsdB binding, the S. aureus hemoglobin receptor. Escape mutations arose over the course of evolutionary time that reduce IsdB binding, and IsdB preferentially binds modern human hemoglobin, consistent with S. aureus evolving to infect humans. Together, this Thesis identifies key mechanisms by which S. aureus acquires and synthesizes heme to support physiology and pathogenesis.