LL-37-mediated activation of host receptors is critical for defense against group A streptococcal infection
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:34 |
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| Enthalten in: |
Cell reports - 34(2021), 9 vom: 02. März, Seite 108766 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Biswas, Debabrata [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 25.01.2022 Date Revised 26.02.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.1016/j.celrep.2021.108766 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM322148375 |
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| 500 | |a Date Revised 26.02.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a CRAMP | |
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| 650 | 4 | |a GAS | |
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| 650 | 4 | |a host-defense peptides | |
| 650 | 4 | |a innate immunity | |
| 650 | 4 | |a murine models of human GAS soft-tissue infections | |
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| 650 | 7 | |a ErbB Receptors |2 NLM | |
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| 650 | 7 | |a Serine Endopeptidases |2 NLM | |
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| 700 | 1 | |a Ravins, Miriam |e verfasserin |4 aut | |
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| 700 | 1 | |a Sharma, Abhinay |e verfasserin |4 aut | |
| 700 | 1 | |a Lim, Kimberly Xuan Zhen |e verfasserin |4 aut | |
| 700 | 1 | |a Tan, Rachel Ying Min |e verfasserin |4 aut | |
| 700 | 1 | |a Lim, Hwee Ying |e verfasserin |4 aut | |
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| 700 | 1 | |a Bachrach, Gilad |e verfasserin |4 aut | |
| 700 | 1 | |a Angeli, Veronique |e verfasserin |4 aut | |
| 700 | 1 | |a Hanski, Emanuel |e verfasserin |4 aut | |
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