LL-37-mediated activation of host receptors is critical for defense against group A streptococcal infection

Debabrata Biswas*, Poornima Ambalavanan, Miriam Ravins, Aparna Anand, Abhinay Sharma, Kimberly Xuan Zhen Lim, Rachel Ying Min Tan, Hwee Ying Lim, Asaf Sol, Gilad Bachrach, Veronique Angeli, Emanuel Hanski*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

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. The host-defense peptide LL-37 protects the host against group A Streptococcus (GAS) infections. Biswas et al. demonstrate that GAS ScpC protease cleaves LL-37. The cleavage abrogates LL-37-mediated activation of P2X7R and EGFR. Treating mice with sub-bactericidal concentrations of non-cleavable LL-37 analogs promotes GAS clearance, abolished by P2X7R or EGFR antagonists.

Original languageAmerican English
Article number108766
JournalCell Reports
Volume34
Issue number9
DOIs
StatePublished - 2 Mar 2021

Bibliographical note

Publisher Copyright:
© 2021 The Authors

Keywords

  • CRAMP
  • EGFR
  • GAS
  • LL-37
  • P2X7R
  • group A Streptococcus
  • host-defense peptides
  • innate immunity
  • murine models of human GAS soft-tissue infections
  • neutrophils

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