title: Genome-wide protective response used by group A Streptococcus to evade destruction by human polymorphonuclear leukocytes.
abstract: Group A Streptococcus (GAS) evades polymorphonuclear leukocyte (PMN) phagocytosis and killing to cause human disease, including pharyngitis and necrotizing fasciitis (flesh-eating syndrome). We show that GAS genes differentially regulated during phagocytic interaction with human PMNs comprise a global pathogen-protective response to innate immunity. GAS prophage genes and genes involved in virulence, oxidative stress, cell wall biosynthesis, and gene regulation were up-regulated during PMN phagocytosis. Genes encoding novel secreted proteins were up-regulated, and the proteins were produced during human GAS infections. We discovered an essential role for the Ihk-Irr two-component regulatory system in evading PMN-mediated killing and promoting host-cell lysis, processes that would facilitate GAS pathogenesis. Importantly, the irr gene was highly expressed during human GAS pharyngitis. We conclude that a complex pathogen genetic program circumvents human innate immunity to promote disease. The gene regulatory program revealed by our studies identifies previously undescribed potential vaccine antigens and targets for therapeutic interventions designed to control GAS infections.
authors.affiliation: Laboratory of Human Bacterial Pathogenesis, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA.
authors.forename: Jovanka M
authors.initials: JM
authors.lastname: Voyich
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Sturdevant
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Braughton
authors.forename: Scott D
authors.initials: SD
authors.lastname: Kobayashi
authors.forename: Benfang
authors.initials: B
authors.lastname: Lei
authors.forename: Kimmo
authors.initials: K
authors.lastname: Virtaneva
authors.forename: David W
authors.initials: DW
authors.lastname: Dorward
authors.forename: James M
authors.initials: JM
authors.lastname: Musser
authors.forename: Frank R
authors.initials: FR
authors.lastname: DeLeo
mesh_terms: D015964:Gene Expression Regulation, Bacterial; D005798:Genes, Bacterial; D016680:Genome, Bacterial; D006801:Humans; D009504:Neutrophils / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D010587:Phagocytosis; D013297:Streptococcus pyogenes / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D014158:Transcription, Genetic; D015854:Up-Regulation; D014774:Virulence / Q000235:genetics