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

Hollands, Andrew; Gonzalez, David J.; Leire, Emma; Donald, Cortny A.; Gallo, Richard L.; Sanderson-Smith, Martina L.; Dorrestein, Pieter C.; Nizet, Victor

doi:10.1074/jbc.m112.404582

Cited by 40 publications

(43 citation statements)

References 28 publications

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“…Consistent with previous reports for other GAS strains (30,35), we found that LL-37 had antimicrobial activity for GAS strain 854, with an MIC of 50 M and an MBC of 20 -30 M. The slightly lower concentration of peptide required for killing compared with that for inhibition of growth reflects the different conditions of the two assays: the killing assay was performed under hypotonic conditions that enhance antimicrobial activity. FK-16, which corresponds to the region considered to encompass the core of LL-37 antimicrobial activity (19,20), demonstrated more potent antimicrobial activity than fulllength LL-37, with lower MIC and MBC of 1 and 0.75-1 M, respectively.…”

Section: Mics and Mbcs Of Ll-37 And Itssupporting

confidence: 90%

The Human Antimicrobial Peptide LL-37 Binds Directly to CsrS, a Sensor Histidine Kinase of Group A Streptococcus, to Activate Expression of Virulence Factors

Velarde

Ashbaugh

Wessels

2014

Journal of Biological Chemistry

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Background: Group A Streptococcus responds to the human antimicrobial peptide LL-37 by up-regulating virulence factors controlled by the CsrRS system. Results: We provide genetic and biochemical evidence for direct binding between LL-37 and the CsrS receptor. Conclusion: LL-37 signaling through CsrS is mediated by a direct binding interaction. Significance: These findings advance our understanding of streptococcal virulence regulation in response to a host signal.

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Section: Mics and Mbcs Of Ll-37 And Itssupporting

confidence: 90%

The Human Antimicrobial Peptide LL-37 Binds Directly to CsrS, a Sensor Histidine Kinase of Group A Streptococcus, to Activate Expression of Virulence Factors

Velarde

Ashbaugh

Wessels

2014

Journal of Biological Chemistry

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“…The acquisition of plasmin protease activity on the GAS cell surface plays a key role in GAS pathogenesis (258). GAS surface-bound plasmin activity was recently demonstrated to promote degradation of human cathelicidin LL-37 (259). SIC also binds and inhibits antimicrobial peptide LL-37 (213-215).…”

Section: Resistance To Antimicrobial Peptidesmentioning

confidence: 99%

Disease Manifestations and Pathogenic Mechanisms of Group A Streptococcus

et al. 2014

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SUMMARY Streptococcus pyogenes , also known as group A Streptococcus (GAS), causes mild human infections such as pharyngitis and impetigo and serious infections such as necrotizing fasciitis and streptococcal toxic shock syndrome. Furthermore, repeated GAS infections may trigger autoimmune diseases, including acute poststreptococcal glomerulonephritis, acute rheumatic fever, and rheumatic heart disease. Combined, these diseases account for over half a million deaths per year globally. Genomic and molecular analyses have now characterized a large number of GAS virulence determinants, many of which exhibit overlap and redundancy in the processes of adhesion and colonization, innate immune resistance, and the capacity to facilitate tissue barrier degradation and spread within the human host. This improved understanding of the contribution of individual virulence determinants to the disease process has led to the formulation of models of GAS disease progression, which may lead to better treatment and intervention strategies. While GAS remains sensitive to all penicillins and cephalosporins, rising resistance to other antibiotics used in disease treatment is an increasing worldwide concern. Several GAS vaccine formulations that elicit protective immunity in animal models have shown promise in nonhuman primate and early-stage human trials. The development of a safe and efficacious commercial human vaccine for the prophylaxis of GAS disease remains a high priority.

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

Cited by 40 publications

References 28 publications

The Human Antimicrobial Peptide LL-37 Binds Directly to CsrS, a Sensor Histidine Kinase of Group A Streptococcus, to Activate Expression of Virulence Factors

The Human Antimicrobial Peptide LL-37 Binds Directly to CsrS, a Sensor Histidine Kinase of Group A Streptococcus, to Activate Expression of Virulence Factors

Disease Manifestations and Pathogenic Mechanisms of Group A Streptococcus

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

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