Impact of Heme During Group A Streptococcus Infection

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Project Summary The overarching goal of this collaborative project is to define the role of heme in the pathophysiology of the Group A Streptococcus (GAS) with the aim of developing new treatment modalities. In the human host, heme has two roles: both a critical nutrient and a noxious agent. Thus, for the β-hemolytic GAS, heme management requires a delicate balancing act. We hypothesize that GAS carefully monitors the levels of heme in both the extracellular and intracellular compartments and accordingly deploys heme uptake and use or detoxification and repair pathways. Furthermore, we propose that GAS uses heme-sensitive regulatory proteins to influence the expression of both iron-homeostasis and virulence genes. In this application, two experienced GAS researchers (MPIs Eichenbaum and McIver) will combine molecular genetic and biochemical methods with transcriptome studies and genome-wide mutagenesis screens to identify and characterize GAS mechanisms for heme management and establish their role in GAS pathogenesis; We describe key heme uptake pathways and GAS pathophysiology (Aim 1); characterize the mechanisms that facilitate heme resistance in the GAS envelope (Aim 2); and analyze the regulatory framework that orchestrates GAS adaptation according to environmental heme (Aim 3). This project will help reveal the fundamental impact of heme in the pathophysiology of a major human pathogen.