title: Analysis of the transcriptome of group A Streptococcus in mouse soft tissue infection.
abstract: Molecular mechanisms mediating group A Streptococcus (GAS)-host interactions remain poorly understood but are crucial for diagnostic, therapeutic, and vaccine development. An optimized high-density microarray was used to analyze the transcriptome of GAS during experimental mouse soft tissue infection. The transcriptome of a wild-type serotype M1 GAS strain and an isogenic transcriptional regulator knockout mutant (covR) also were compared. Array datasets were verified by quantitative real-time reverse transcriptase-polymerase chain reaction and in situ immunohistochemistry. The results unambiguously demonstrate that coordinated expression of proven and putative GAS virulence factors is directed toward overwhelming innate host defenses leading to severe cellular damage. We also identified adaptive metabolic responses triggered by nutrient signals and hypoxic/acidic conditions in the host, likely facilitating pathogen persistence and proliferation in soft tissues. Key discoveries included that oxidative stress genes, virulence genes, genes related to amino acid and maltodextrin utilization, and several two-component transcriptional regulators were highly expressed in vivo. This study is the first global analysis of the GAS transcriptome during invasive infection. Coupled with parallel analysis of the covR mutant strain, novel insights have been made into the regulation of GAS virulence in vivo, resulting in new avenues for targeted therapeutic and vaccine research.
authors.affiliation: Laboratory of Human Bacterial Pathogenesis, Rocky Mountain Veterinary Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA.
authors.forename: Morag R
authors.initials: MR
authors.lastname: Graham
authors.forename: Kimmo
authors.initials: K
authors.lastname: Virtaneva
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Porcella
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Gardner
authors.forename: R Daniel
authors.initials: RD
authors.lastname: Long
authors.forename: Diane M
authors.initials: DM
authors.lastname: Welty
authors.forename: William T
authors.initials: WT
authors.lastname: Barry
authors.forename: Claire A
authors.initials: CA
authors.lastname: Johnson
authors.forename: Larye D
authors.initials: LD
authors.lastname: Parkins
authors.forename: Fred A
authors.initials: FA
authors.lastname: Wright
authors.forename: James M
authors.initials: JM
authors.lastname: Musser
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics*; D020869:Gene Expression Profiling; D015964:Gene Expression Regulation, Bacterial / Q000235:genetics*; D007113:Immunity, Innate / Q000235:genetics; D051379:Mice; D018384:Oxidative Stress / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics*; D018461:Soft Tissue Infections / Q000235:genetics* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D013290:Streptococcal Infections / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D022541:Streptococcal Vaccines / Q000235:genetics; D013297:Streptococcus pyogenes / Q000235:genetics* / Q000472:pathogenicity; D014158:Transcription, Genetic / Q000235:genetics; D014611:Vaccination; D037521:Virulence Factors / Q000096:biosynthesis*
chemical_list: D001426:Bacterial Proteins; C432143:CsrR protein, Streptococcus pyogenes; D012097:Repressor Proteins; D022541:Streptococcal Vaccines; D037521:Virulence Factors