title: Iron Efflux by PmtA Is Critical for Oxidative Stress Resistance and Contributes Significantly to Group A Streptococcus Virulence.
abstract: Group AStreptococcus(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 ofpmtAis specifically induced by excess iron, and this induction requires PerR. Furthermore, apmtAmutant 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.
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, and Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Arica R
authors.initials: AR
authors.lastname: VanderWal
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, and Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Nishanth
authors.initials: N
authors.lastname: Makthal
authors.affiliation: Department of Microbiology, Cornell University, Ithaca, New York, USA.
authors.forename: Azul
authors.initials: A
authors.lastname: Pinochet-Barros
authors.affiliation: Department of Microbiology, Cornell University, Ithaca, New York, USA.
authors.forename: John D
authors.identifier: http://orcid.org/0000-0002-3832-3249
authors.initials: JD
authors.lastname: Helmann
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, and Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Olsen
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, and Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas, USA mkumaraswami@houstonmethodist.org.
authors.forename: Muthiah
authors.initials: M
authors.lastname: Kumaraswami
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015964:Gene Expression Regulation, Bacterial; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018384:Oxidative Stress; D012329:RNA, Bacterial / Q000235:genetics; D018085:Regulon; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013290:Streptococcal Infections / Q000235:genetics / Q000382:microbiology; D013297:Streptococcus pyogenes / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D014774:Virulence
chemical_list: D001426:Bacterial Proteins; D012329:RNA, Bacterial; D012097:Repressor Proteins; C122138:peroxide repressor proteins; D006861:Hydrogen Peroxide; D008780:Methyltransferases; C435200:PmtA protein, bacteria
keywords: bacterial pathogenesis; gene regulation; iron efflux; metal homeostasis; oxidative stress