title: Streptococcal inhibitor of complement promotes innate immune resistance phenotypes of invasive M1T1 group A Streptococcus.
abstract: Streptococcal inhibitor of complement (SIC) is a highly polymorphic extracellular protein and putative virulence factor secreted by M1 and M57 strains of group A Streptococcus (GAS). The sic gene is highly upregulated in invasive M1T1 GAS isolates following selection of mutations in the covR/S regulatory locus in vivo. Previous work has shown that SIC (allelic form 1.01) binds to and inactivates complement C5b67 and human cathelicidin LL-37. We examined the contribution of SIC to innate immune resistance phenotypes of GAS in the intact organism, using (1) targeted deletion of sic in wild-type and animal-passaged (covS mutant) M1T1 GAS harboring the sic 1.84 allele and (2) heterologous expression of sic in M49 GAS, which does not possess the sic genein its genome. We find that M1T1 SIC production is strongly upregulated upon covS mutation but that the sic gene is not required for generation and selection of covS mutants in vivo. SIC 1.84 bound both human and murine cathelicidins and was necessary and sufficient to promote covS mutant M1T1 GAS resistance to LL-37, growth in human whole blood and virulence in a murine model of systemic infection. Finally, the sic knockout mutant M1T1 GAS strain was deficient in growth in human serum and intracellular macrophage survival. We conclude that SIC contributes to M1T1 GAS immune resistance and virulence phenotypes.
authors.affiliation: Biomedical Sciences Graduate Program, Department of Pediatrics, University of California San Diego, San Diego, CA 92093-0687, USA.
authors.forename: Morgan A
authors.initials: MA
authors.lastname: Pence
authors.forename: Suzan H M
authors.initials: SH
authors.lastname: Rooijakkers
authors.forename: Anna L
authors.initials: AL
authors.lastname: Cogen
authors.forename: Jason N
authors.initials: JN
authors.lastname: Cole
authors.forename: Andrew
authors.initials: A
authors.lastname: Hollands
authors.forename: Richard L
authors.initials: RL
authors.lastname: Gallo
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D001433:Bacteriolysis / Q000235:genetics; D054804:Cathelicidins / Q000276:immunology / Q000378:metabolism*; D048708:Cell Growth Processes / Q000235:genetics; D002478:Cells, Cultured; D003001:Cloning, Molecular; D015964:Gene Expression Regulation, Bacterial; D055786:Gene Knockout Techniques; D000071677:Histidine Kinase; D006801:Humans; D057131:Immune Evasion / Q000235:genetics; D007113:Immunity, Innate; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D013045:Species Specificity; D013290:Streptococcal Infections / Q000276:immunology* / Q000382:microbiology / Q000503:physiopathology; D013297:Streptococcus pyogenes / Q000472:pathogenicity / Q000502:physiology*; D019076:Transgenes / Q000235:genetics; D014774:Virulence / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D054804:Cathelicidins; D047908:Intracellular Signaling Peptides and Proteins; C097739:SIC protein, Streptococcus; C534547:CovS protein, Streptococcus pyogenes; D000071677:Histidine Kinase
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