title: PerR confers phagocytic killing resistance and allows pharyngeal colonization by group A Streptococcus.
abstract: The peroxide response transcriptional regulator, PerR, is thought to contribute to virulence of group A Streptococcus (GAS); however, the specific mechanism through which it enhances adaptation for survival in the human host remains unknown. Here, we identify a critical role of PerR-regulated gene expression in GAS phagocytosis resistance and in virulence during pharyngeal infection. Deletion of perR in M-type 3 strain 003Sm was associated with reduced resistance to phagocytic killing in human blood and by murine macrophages in vitro. The increased phagocytic killing of the perR mutant was abrogated in the presence of the general oxidative burst inhibitor diphenyleneiodonium chloride (DPI), a result that suggests PerR-dependent gene expression counteracts the phagocyte oxidative burst. Moreover, an isogenic perR mutant was severely attenuated in a baboon model of GAS pharyngitis. In competitive infection experiments, the perR mutant was cleared from two animals at 24 h and from four of five animals by day 14, in sharp contrast to wild-type bacteria that persisted in the same five animals for 28 to 42 d. GAS genomic microarrays were used to compare wild-type and perR mutant transcriptomes in order to characterize the PerR regulon of GAS. These studies identified 42 PerR-dependent loci, the majority of which had not been previously recognized. Surprisingly, a large proportion of these loci are involved in sugar utilization and transport, in addition to oxidative stress adaptive responses and virulence. This finding suggests a novel role for PerR in mediating sugar uptake and utilization that, together with phagocytic killing resistance, may contribute to GAS fitness in the infected host. We conclude that PerR controls expression of a diverse regulon that enhances GAS resistance to phagocytic killing and allows adaptation for survival in the pharynx.
authors.affiliation: Division of Infectious Diseases, Children's Hospital Boston, Massachusetts, United States of America.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Gryllos
authors.forename: Renata
authors.initials: R
authors.lastname: Grifantini
authors.forename: Annalisa
authors.initials: A
authors.lastname: Colaprico
authors.forename: Max E
authors.initials: ME
authors.lastname: Cary
authors.forename: Anders
authors.initials: A
authors.lastname: Hakansson
authors.forename: David W
authors.initials: DW
authors.lastname: Carey
authors.forename: Maria
authors.initials: M
authors.lastname: Suarez-Chavez
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Kalish
authors.forename: Paul D
authors.initials: PD
authors.lastname: Mitchell
authors.forename: Gary L
authors.initials: GL
authors.lastname: White
authors.forename: Michael R
authors.initials: MR
authors.lastname: Wessels
mesh_terms: D001426:Bacterial Proteins / Q000502:physiology*; D050260:Carbohydrate Metabolism / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D050296:Microbial Viability / Q000235:genetics; D018384:Oxidative Stress / Q000235:genetics; D010614:Pharynx; D012097:Repressor Proteins / Q000502:physiology*; D013297:Streptococcus pyogenes / Q000235:genetics / Q000472:pathogenicity*; D014157:Transcription Factors / Q000502:physiology*; D014774:Virulence / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C122138:peroxide repressor proteins
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