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Published on: August 19, 2016
Streptococcal inhibitor of complement promotes innate immune resistance phenotypes of invasive M1T1 group A
Morgan A Pence1, Suzan H M Rooijakkers, Anna L Cogen
1Biomedical Sciences Graduate Program, Department of Pediatrics, University of California San Diego, San Diego, CA 92093-0687, USA.
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.
Insights
Streptococcal inhibitor of complement (SIC) protein enhances Group A Streptococcus (GAS) virulence by resisting host immune defenses. SIC is crucial for M1T1 GAS survival against cathelicidins and in host environments.
Area of Science:
- Microbiology
- Immunology
- Molecular Biology
Background:
- Streptococcal inhibitor of complement (SIC) is an extracellular protein and virulence factor in Group A Streptococcus (GAS).
- SIC is secreted by M1 and M57 GAS strains and its gene (sic) is upregulated in invasive isolates.
- Previous studies show SIC (allelic form 1.01) inhibits complement C5b67 and cathelicidin LL-37.
Purpose of the Study:
- To investigate the role of SIC in the innate immune resistance of GAS.
- To determine SIC's contribution to GAS virulence phenotypes in vivo.
Main Methods:
- Targeted deletion of the sic gene in wild-type and covS mutant M1T1 GAS strains (sic 1.84 allele).
- Heterologous expression of sic in M49 GAS (which lacks the sic gene).
- Assessed SIC binding to cathelicidins and GAS resistance to LL-37, human whole blood, human serum, and macrophage survival.
Main Results:
- SIC production is upregulated in covS mutant M1T1 GAS, but sic is not essential for covS mutant selection in vivo.
- SIC 1.84 binds human and murine cathelicidins, conferring resistance to LL-37, promoting growth in human blood, and enhancing virulence in a murine infection model.
- sic knockout M1T1 GAS showed reduced growth in human serum and impaired intracellular macrophage survival.
Conclusions:
- SIC is essential for M1T1 GAS resistance to host immune factors, including cathelicidins and serum.
- SIC significantly contributes to the virulence of M1T1 GAS in systemic infections.
- SIC is a key factor in GAS immune evasion and pathogenesis.
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