Inactivation of the antifungal and immunomodulatory properties of human cathelicidin LL-37 by aspartic proteases produced by the pathogenic yeast Candida albicans
| Autor: | Natalia Wolak, Maria Rapala-Kozik, Oliwia Bochenska, Marcin Zawrotniak, Wataru Aoki, Mitsuyoshi Ueda, Andrzej Kozik, Dominika Ostrowska, Grzegorz Trebacz, Mariusz Gogol |
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| Rok vydání: | 2015 |
| Předmět: |
Antifungal Agents
Aspartic Acid Proteases Neutrophils medicine.medical_treatment Immunology Microbiology Receptors Interleukin-8B Cathelicidin Cell Movement Cathelicidins Candida albicans medicine Humans Immunologic Factors Amino Acid Sequence Pathogen Caspase Host Response and Inflammation biology Dose-Response Relationship Drug Chemotaxis biology.organism_classification Antimicrobial Corpus albicans Coculture Techniques Infectious Diseases Biochemistry Gene Expression Regulation Caspases biology.protein Parasitology Reactive Oxygen Species Antimicrobial Cationic Peptides |
| Zdroj: | Infection and immunity. 83(6) |
| ISSN: | 1098-5522 |
| Popis: | Constant cross talk between Candida albicans yeast cells and their human host determines the outcome of fungal colonization and, eventually, the progress of infectious disease (candidiasis). An effective weapon used by C. albicans to cope with the host defense system is the release of 10 distinct secreted aspartic proteases (SAPs). Here, we validate a hypothesis that neutrophils and epithelial cells use the antimicrobial peptide LL-37 to inactivate C. albicans at sites of candidal infection and that C. albicans uses SAPs to effectively degrade LL-37. LL-37 is cleaved into multiple products by SAP1 to -4, SAP8, and SAP9, and this proteolytic processing is correlated with the gradual decrease in the antifungal activity of LL-37. Moreover, a major intermediate of LL-37 cleavage—the LL-25 peptide—is antifungal but devoid of the immunomodulatory properties of LL-37. In contrast to LL-37, LL-25 did not affect the generation of reactive oxygen species by neutrophils upon treatment with phorbol esters. Stimulating neutrophils with LL-25 (rather than LL-37) significantly decreased calcium flux and interleukin-8 production, resulting in lower chemotactic activity of the peptide against neutrophils, which may decrease the recruitment of neutrophils to infection foci. LL-25 also lost the function of LL-37 as an inhibitor of neutrophil apoptosis, thereby reducing the life span of these defense cells. This study indicates that C. albicans can effectively use aspartic proteases to destroy the antimicrobial and immunomodulatory properties of LL-37, thus enabling the pathogen to survive and propagate. |
| Databáze: | OpenAIRE |
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