Group A Streptococcus (GAS) is a human-only pathogen that causes a spectrum of disease conditions. Given its survival in inflamed lesions, the ability to sense and overcome oxidative stress is critical for GAS pathogenesis. PerR senses oxidative stress and coordinates the regulation of genes involved in GAS
antioxidant defenses. In this study, we investigated the role of PerR-controlled
metal transporter A (PmtA) in GAS pathogenesis. Previously, PmtA was implicated in GAS
antioxidant defenses and suggested to protect against
zinc toxicity. Here, we report that PmtA is a P1B4-type
ATPase that functions as an Fe(II) exporter and
aids GAS defenses against
iron intoxication and oxidative stress. The expression of pmtA is specifically induced by excess
iron, and this induction requires PerR. Furthermore, a pmtA mutant exhibited increased sensitivity to
iron toxicity and oxidative stress due to an elevated intracellular accumulation of
iron.
RNA-sequencing analysis revealed that GAS undergoes significant alterations in gene expression to adapt to
iron toxicity. Finally, using two mouse models of invasive
infection, we demonstrated that
iron efflux by PmtA is critical for bacterial survival during
infection and GAS virulence. Together, these data demonstrate that PmtA is a key component of GAS
antioxidant defenses and contributes significantly to GAS virulence.