title: The Staphylococcus aureus ABC-Type Manganese Transporter MntABC Is Critical for Reinitiation of Bacterial Replication Following Exposure to Phagocytic Oxidative Burst.
abstract: Manganese plays a central role in cellular detoxification of reactive oxygen species (ROS). Therefore, manganese acquisition is considered to be important for bacterial pathogenesis by counteracting the oxidative burst of phagocytic cells during host infection. However, detailed analysis of the interplay between bacterial manganese acquisition and phagocytic cells and its impact on bacterial pathogenesis has remained elusive for Staphylococcus aureus, a major human pathogen. Here, we show that a mntC mutant, which lacks the functional manganese transporter MntABC, was more sensitive to killing by human neutrophils but not murine macrophages, unless the mntC mutant was pre-exposed to oxidative stress. Notably, the mntC mutant formed strikingly small colonies when recovered from both type of phagocytic cells. We show that this phenotype is a direct consequence of the inability of the mntC mutant to reinitiate growth after exposure to phagocytic oxidative burst. Transcript and quantitative proteomics analyses revealed that the manganese-dependent ribonucleotide reductase complex NrdEF, which is essential for DNA synthesis and repair, was highly induced in the mntC mutant under oxidative stress conditions including after phagocytosis. Since NrdEF proteins are essential for S. aureus viability we hypothesize that cells lacking MntABC might attempt to compensate for the impaired function of NrdEF by increasing their expression. Our data suggest that besides ROS detoxification, functional manganese acquisition is likely crucial for S. aureus pathogenesis by repairing oxidative damages, thereby ensuring efficient bacterial growth after phagocytic oxidative burst, which is an attribute critical for disseminating and establishing infection in the host.
authors.affiliation: Department of Infectious Diseases, Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Alison
authors.initials: A
authors.lastname: Coady
authors.affiliation: Department of Translational Immunology, Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Protein Chemistry, Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Qui
authors.initials: Q
authors.lastname: Phung
authors.affiliation: Department of Protein Chemistry, Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Tommy K
authors.initials: TK
authors.lastname: Cheung
authors.affiliation: Department of Protein Chemistry, Genentech Inc., South San Francisco, California, United States of America; Department of Bioinformatics, Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Corey
authors.initials: C
authors.lastname: Bakalarski
authors.affiliation: Department of Infectious Diseases, Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Mary Kate
authors.initials: MK
authors.lastname: Alexander
authors.affiliation: Department of Infectious Diseases, Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Sophie M
authors.initials: SM
authors.lastname: Lehar
authors.affiliation: Department of Translational Immunology, Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Janice
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Translational Immunology, Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Summer
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Infectious Diseases, Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Man-Wah
authors.initials: MW
authors.lastname: Tan
authors.affiliation: Department of Infectious Diseases, Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Mireille
authors.initials: M
authors.lastname: Nishiyama
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics*; D015964:Gene Expression Regulation, Bacterial / Q000235:genetics; D006801:Humans; D008264:Macrophages / Q000382:microbiology; D008345:Manganese / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000235:genetics*; D051379:Mice; D009504:Neutrophils / Q000382:microbiology; D018384:Oxidative Stress / Q000235:genetics*; D010587:Phagocytosis / Q000235:genetics; D040901:Proteomics / Q000379:methods; D017382:Reactive Oxygen Species / Q000378:metabolism; D016897:Respiratory Burst / Q000235:genetics*; D013203:Staphylococcal Infections / Q000382:microbiology; D013211:Staphylococcus aureus / Q000235:genetics* / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D026901:Membrane Transport Proteins; D017382:Reactive Oxygen Species; D008345:Manganese