Journal of Innate Immunity

Research Article

Free Access

Streptococcal Inhibitor of Complement Promotes Innate Immune Resistance Phenotypes of Invasive M1T1 Group A Streptococcus

Pence M.A.a, b · Rooijakkers S.H.M.b, h · Cogen A.L.c · Cole J.N.b, g · Hollands A.b, g · Gallo R.L.b, c, f · Nizet V.b, d, e

Author affiliations

aBiomedical Sciences Graduate Program, Departments of bPediatrics and cMedicine, dSkaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, and eRady Children’s Hospital, San Diego, Calif., and fVA San Diego Health Care System, La Jolla, Calif., USA; gSchool of Biological Sciences, University of Wollongong, Wollongong, N.S.W., Australia; hDepartment of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands

Corresponding Author

Prof. Victor Nizet, Department of Pediatrics, School of Medicine

Skaggs School of Pharmacy and Pharmaceutical Sciences

University of California San Diego

9500 Gilman Drive, Mail Code 0687, La Jolla, CA 92093-0687 (USA)

Tel. +1 858 534 7408, Fax +1 858 534 5611, E-Mail vnizet@ucsd.edu

Keywords: Complement systemInnate immunityStreptococcusVirulence factorsCathelicidinAntimicrobial peptides

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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.

© 2010 S. Karger AG, Basel



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Article / Publication Details

First-Page Preview
Abstract of Research Article

Received: February 03, 2010
Accepted: June 13, 2010
Published online: September 01, 2010
Issue release date: October 2010

Number of Print Pages: 9
Number of Figures: 4
Number of Tables: 1

ISSN: 1662-811X (Print)
eISSN: 1662-8128 (Online)

For additional information: https://www.karger.com/JIN

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