title: Streptococcal collagen-like protein A and general stress protein 24 are immunomodulating virulence factors of group A Streptococcus.
abstract: In Western countries, invasive infections caused by M1T1 serotype group A Streptococcus (GAS) are epidemiologically linked to mutations in the control of virulence regulatory 2-component operon (covRS). In indigenous communities and developing countries, severe GAS disease is associated with genetically diverse non-M1T1 GAS serotypes. Hypervirulent M1T1 covRS mutant strains arise through selection by human polymorphonuclear cells for increased expression of GAS virulence factors such as the DNase Sda1, which promotes neutrophil resistance. The GAS bacteremia isolate NS88.2 (emm 98.1) is a covS mutant that exhibits a hypervirulent phenotype and neutrophil resistance yet lacks the phage-encoded Sda1. Here, we have employed a comprehensive systems biology (genomic, transcriptomic, and proteomic) approach to identify NS88.2 virulence determinants that enhance neutrophil resistance in the non-M1T1 GAS genetic background. Using this approach, we have identified streptococcal collagen-like protein A and general stress protein 24 proteins as NS88.2 determinants that contribute to survival in whole blood and neutrophil resistance in non-M1T1 GAS. This study has revealed new factors that contribute to GAS pathogenicity that may play important roles in resisting innate immune defenses and the development of human invasive infections.
authors.affiliation: Illawarra Health and Medical Research Institute, and School of Biological Sciences, University of Wollongong, Wollongong, NSW, 2522, Australia.
authors.forename: James A
authors.initials: JA
authors.lastname: Tsatsaronis
authors.forename: Andrew
authors.initials: A
authors.lastname: Hollands
authors.forename: Jason N
authors.initials: JN
authors.lastname: Cole
authors.forename: Peter G
authors.initials: PG
authors.lastname: Maamary
authors.forename: Christine M
authors.initials: CM
authors.lastname: Gillen
authors.forename: Nouri L
authors.initials: NL
authors.lastname: Ben Zakour
authors.forename: Malak
authors.initials: M
authors.lastname: Kotb
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.forename: Scott A
authors.initials: SA
authors.lastname: Beatson
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Walker
authors.forename: Martina L
authors.initials: ML
authors.lastname: Sanderson-Smith
mesh_terms: D000818:Animals; D001422:Bacterial Adhesion / Q000235:genetics / Q000276:immunology; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D015180:Electrophoresis, Gel, Two-Dimensional; D020869:Gene Expression Profiling; D015964:Gene Expression Regulation, Bacterial; D016680:Genome, Bacterial / Q000235:genetics; D023281:Genomics / Q000379:methods; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D051379:Mice; D050296:Microbial Viability / Q000235:genetics / Q000276:immunology; D009154:Mutation; D018375:Neutrophil Activation / Q000276:immunology; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D020411:Oligonucleotide Array Sequence Analysis; D020543:Proteome / Q000235:genetics / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013290:Streptococcal Infections / Q000097:blood / Q000276:immunology* / Q000382:microbiology; D013297:Streptococcus pyogenes / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D014774:Virulence / Q000235:genetics / Q000276:immunology
chemical_list: D001426:Bacterial Proteins; D020543:Proteome; C583454:Streptococcal collagen-like protein A, Streptococcus pyrogenes; C583455:gls24 protein, Streptococcus pyrogenes
keywords: innate immunity; next-generation sequencing; systems biology