1. LL-37-mediated activation of host receptors is critical for defense against group A streptococcal infection.
- Author
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Biswas D, Ambalavanan P, Ravins M, Anand A, Sharma A, Lim KXZ, Tan RYM, Lim HY, Sol A, Bachrach G, Angeli V, and Hanski E
- Subjects
- Animals, Anti-Bacterial Agents pharmacology, Antimicrobial Cationic Peptides pharmacology, Bacterial Proteins metabolism, Cathelicidins genetics, Cathelicidins metabolism, Cell Line, Disease Models, Animal, Female, Host-Pathogen Interactions, Humans, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Neutrophils drug effects, Neutrophils metabolism, Serine Endopeptidases metabolism, Signal Transduction, Streptococcal Infections drug therapy, Streptococcal Infections genetics, Streptococcal Infections metabolism, Streptococcus pyogenes enzymology, Streptococcus pyogenes genetics, Substrate Specificity, Mice, Antimicrobial Cationic Peptides metabolism, ErbB Receptors metabolism, Neutrophils microbiology, Receptors, Purinergic P2X7 metabolism, Streptococcal Infections microbiology, Streptococcus pyogenes pathogenicity
- Abstract
Group A Streptococcus (GAS) causes diverse human diseases, including life-threatening soft-tissue infections. It is accepted that the human antimicrobial peptide LL-37 protects the host by killing GAS. Here, we show that GAS extracellular protease ScpC N-terminally cleaves LL-37 into two fragments of 8 and 29 amino acids, preserving its bactericidal activity. At sub-bactericidal concentrations, the cleavage inhibits LL-37-mediated neutrophil chemotaxis, shortens neutrophil lifespan, and eliminates P2X7 and EGF receptors' activation. Mutations at the LL-37 cleavage site protect the peptide from ScpC-mediated splitting, maintaining all its functions. The mouse LL-37 ortholog CRAMP is neither cleaved by ScpC nor does it activate P2X7 or EGF receptors. Treating wild-type or CRAMP-null mice with sub-bactericidal concentrations of the non-cleavable LL-37 analogs promotes GAS clearance that is abolished by the administration of either P2X7 or EGF receptor antagonists. We demonstrate that LL-37-mediated activation of host receptors is critical for defense against GAS soft-tissue infections., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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