Streptococcal Inhibitor of Complement Promotes Innate Immune Resistance Phenotypes of Invasive M1T1 Group A &lt;i&gt;Streptococcus&lt;/i&gt;

Pence, Morgan A.; Rooijakkers, Suzan H. M.; Cogen, Anna L.; Cole, Jason N.; Hollands, Andrew; Gallo, Richard L.; Nizet, Victor

doi:10.1159/000317672

Cited by 47 publications

(35 citation statements)

References 61 publications

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“…The invasive M1T1 clone of GAS demonstrates increased resistance to cathelicidin AMPs when compared with other GAS strains (22), which may in part be attributable to cathelicidin binding properties of the M1 protein hypervariable domain (22) or protein SIC (streptococcal inhibitor of complement) uniquely expressed only in M1 and M57 strains (23). Upon selection of the covS mutations associated with the shift to invasive infection (2, 4), GAS increases expression of the hyaluronic acid capsule, which can impair cathelicidin killing, (17) and accumulates more plasmin activity on its surface (5).…”

Section: Discussionmentioning

confidence: 99%

A Bacterial Pathogen Co-opts Host Plasmin to Resist Killing by Cathelicidin Antimicrobial Peptides

Hollands

Gonzalez

Leire

et al. 2012

Journal of Biological Chemistry

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Background: Group A Streptococcus (GAS) produces streptokinase (Ska), which activates plasminogen to plasmin while binding the host enzyme to the bacterial surface. Results: Ska-activated plasmin can degrade human cathelicidin LL-37, promoting GAS resistance to the antimicrobial peptide. Conclusion: Ska contributes to GAS innate immune evasion and virulence. Significance: A human pathogen can co-opt the activity of a host protease to subvert peptide-based innate immune defense.

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Section: Discussionmentioning

confidence: 99%

A Bacterial Pathogen Co-opts Host Plasmin to Resist Killing by Cathelicidin Antimicrobial Peptides

Hollands

Gonzalez

Leire

et al. 2012

Journal of Biological Chemistry

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“…To combat these defenses, GAS has evolved several strategies to evade and counteract the innate phagocyte immune response (2). A significant portion of the global burden of invasive GAS disease is attributable to the prevalent M1T1 clone (4,5), which encodes multiple immune evasion genes, including factors that impede neutrophil recruitment, limit phagocytosis (6,7), resist antimicrobial peptides (8,9), and degrade NETs (10,11). These multiple immune evasion mechanisms may allow GAS to resist the innate immune defenses of the host and allow the bacteria to produce systemic infections, including infections in previously healthy individuals.…”

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confidence: 99%

Role for Streptococcal Collagen-Like Protein 1 in M1T1 Group A Streptococcus Resistance to Neutrophil Extracellular Traps

et al. 2014

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c Streptococcal collagen-like protein 1 (Scl-1) is one of the most highly expressed proteins in the invasive M1T1 serotype group A Streptococcus (GAS), a globally disseminated clone associated with higher risk of severe invasive infections. Previous studies using recombinant Scl-1 protein suggested a role in cell attachment and binding and inhibition of serum proteins. Here, we studied the contribution of Scl-1 to the virulence of the M1T1 clone in the physiological context of the live bacterium by generating an isogenic strain lacking the scl-1 gene. Upon subcutaneous infection in mice, wild-type bacteria induced larger lesions than the ⌬scl mutant. However, loss of Scl-1 did not alter bacterial adherence to or invasion of skin keratinocytes. We found instead that Scl-1 plays a critical role in GAS resistance to human and murine phagocytic cells, allowing the bacteria to persist at the site of infection. Phenotypic analyses demonstrated that Scl-1 mediates bacterial survival in neutrophil extracellular traps (NETs) and protects GAS from antimicrobial peptides found within the NETs. Additionally, Scl-1 interferes with myeloperoxidase (MPO) release, a prerequisite for NET production, thereby suppressing NET formation. We conclude that Scl-1 is a virulence determinant in the M1T1 GAS clone, allowing GAS to subvert innate immune functions that are critical in clearing bacterial infections.

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“…In addition, S. pyogenes releases protein SIC that inhibits complement activation and neutralizes AMPs (17)(18)(19)(20)(21). Both SpeB and SIC are produced in high amounts during early growth phase (20,22), and both proteins are important for the virulence of S. pyogenes (22)(23)(24)(25)(26)(27).…”

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Constitutive and Inflammation-Dependent Antimicrobial Peptides Produced by Epithelium Are Differentially Processed and Inactivated by the Commensal Finegoldia magna and the Pathogen Streptococcus pyogenes

Frick

Nordin

Baumgarten

et al. 2011

The Journal of Immunology

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Epithelial linings serve as physical barriers and produce antimicrobial peptides (AMPs) to maintain host integrity. Examples are the bactericidal proteins midkine (MK) and BRAK/CXCL14 that are constitutively produced in the skin epidermal layer, where the anaerobic Gram-positive coccoid commensal Finegoldia magna resides. Consequently, this bacterium is likely to encounter both MK and BRAK/CXCL14, making these molecules possible threats to its habitat. In this study, we show that MK expression is upregulated during inflammation, concomitant with a strong downregulation of BRAK/CXCL14, resulting in changed antibacterial conditions. MK, BRAK/CXCL14, and the inflammation-dependent antimicrobial β-defensins human β-defensin (hBD)-2 and hBD-3 all showed bactericidal activity against both F. magna and the virulent pathogen Streptococcus pyogenes at similar concentrations. SufA, a released protease of F. magna, degraded MK and BRAK/CXCL14 but not hBD-2 nor hBD-3. Cleavage was seen at lysine and arginine residues, amino acids characteristic of AMPs. Intermediate SufA-degraded fragments of MK and BRAK/CXCL14 showed stronger bactericidal activity against S. pyogenes than F. magna, thus promoting survival of the latter. In contrast, the cysteine-protease SpeB of S. pyogenes rapidly degraded all AMPs investigated. The proteins FAF and SIC, released by F. magna and S. pyogenes, respectively, neutralized the antibacterial activity of MK and BRAK/CXCL14, protein FAF being the most efficient. Quantitation and colocalization by immunoelectron microscopy demonstrated significant levels and interactions of the molecules in in vivo and ex vivo samples. The findings reflect strategies used by a permanently residing commensal and a virulent pathogen, the latter operating during the limited time course of invasive disease.

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Streptococcal Inhibitor of Complement Promotes Innate Immune Resistance Phenotypes of Invasive M1T1 Group A <i>Streptococcus</i>

Cited by 47 publications

References 61 publications

A Bacterial Pathogen Co-opts Host Plasmin to Resist Killing by Cathelicidin Antimicrobial Peptides

A Bacterial Pathogen Co-opts Host Plasmin to Resist Killing by Cathelicidin Antimicrobial Peptides

Role for Streptococcal Collagen-Like Protein 1 in M1T1 Group A Streptococcus Resistance to Neutrophil Extracellular Traps

Constitutive and Inflammation-Dependent Antimicrobial Peptides Produced by Epithelium Are Differentially Processed and Inactivated by the Commensal Finegoldia magna and the Pathogen Streptococcus pyogenes

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