title: A bacterial pathogen co-opts host plasmin to resist killing by cathelicidin antimicrobial peptides.
abstract: The bacterial pathogen Group A Streptococcus (GAS) colonizes epithelial and mucosal surfaces and can cause a broad spectrum of human disease. Through the secreted plasminogen activator streptokinase (Ska), GAS activates human plasminogen into plasmin and binds it to the bacterial surface. The resulting surface plasmin protease activity has been proposed to play a role in disrupting tissue barriers, promoting invasive spread of the bacterium. We investigated whether this surface protease activity could aid the immune evasion role through degradation of the key innate antimicrobial peptide LL-37, the human cathelicidin. Cleavage products of plasmin-degraded LL-37 were analyzed by matrix-assisted laser desorption ionization mass spectrometry. Ska-deficient GAS strains were generated by targeted allelic exchange mutagenesis and confirmed to lack surface plasmin activity after growth in human plasma or media supplemented with plasminogen and fibrinogen. Loss of surface plasmin activity left GAS unable to efficiently degrade LL-37 and increased bacterial susceptibility to killing by the antimicrobial peptide. When mice infected with GAS were simultaneously treated with the plasmin inhibitor aprotinin, a significant reduction in the size of necrotic skin lesions was observed. Together these data reveal a novel immune evasion strategy of the human pathogen: co-opting the activity of a host protease to evade peptide-based innate host defenses.
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Hollands
authors.forename: David
authors.initials: D
authors.lastname: Gonzalez
authors.forename: Emma
authors.initials: E
authors.lastname: Leire
authors.forename: Cortny
authors.initials: C
authors.lastname: Donald
authors.forename: Richard L
authors.initials: RL
authors.lastname: Gallo
authors.forename: Martina
authors.initials: M
authors.lastname: Sanderson-Smith
authors.forename: Pieter C
authors.initials: PC
authors.lastname: Dorrestein
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D000925:Anticoagulants / Q000737:chemistry; D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins / Q000737:chemistry* / Q000378:metabolism*; D005341:Fibrinolysin / Q000737:chemistry; D006801:Humans; D007107:Immune System; D007113:Immunity, Innate; D007700:Kinetics; D051379:Mice; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D016296:Mutagenesis; D010958:Plasminogen / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013297:Streptococcus pyogenes / Q000378:metabolism; D013300:Streptokinase / Q000737:chemistry / Q000378:metabolism; D037521:Virulence Factors / Q000378:metabolism
chemical_list: D000925:Anticoagulants; D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D037521:Virulence Factors; D010958:Plasminogen; D013300:Streptokinase; D005341:Fibrinolysin