Group A streptococcal PerR coordinates iron and zinc homeostasis through Dpr, aiding in bacterial fitness during endothelial cell infection

Our study combines dual RNA-seq analysis, an endothelial cell infection model, computational predictions, and phenotypic characterization to discover the impact of group A <i>Streptococcus</i> (GAS) PerR on the coordination of iron and zinc homeostasis during infection. We found that PmtA's iron efflux, iron and zinc-chelating ferritin-like Dpr, the AdcR regulon, and zinc efflux are delicately modulated by PerR. We also determined that zinc limitation inside the phagolysosome GAS-containing vacuoles of endothelial cells causes host zinc starvation, resulting in reduced survival of the Δ<i>perR</i> mutant. Consequently, PerR enhances GAS fitness through Dpr during its invasions of human endothelial cells. Our novel findings offer new insights into how GAS combats iron-mediated oxidative stress and zinc homeostasis that may help develop new anti-GAS treatments.