Chemokine CCL28 Is a Potent Therapeutic Agent for Oropharyngeal Candidiasis

is a commensal organism that causes life-threatening or life-altering opportunistic infections. Treatment of infections is limited by the paucity of antifungal drug classes. Naturally occurring antimicrobial peptides are promising agents for drug development. CCL28 is a CC chemokine that is abundant...

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Bibliographic Details
Published in:Antimicrobial agents and chemotherapy 2020-07, Vol.64 (8)
Main Authors: He, Jie, Thomas, Monica A, de Anda, Jaime, Lee, Michelle W, Van Why, Emma, Simpson, Pippa, Wong, Gerard C L, Grayson, Mitchell H, Volkman, Brian F, Huppler, Anna R
Format: Article
Language:English
Subjects:
Animals
Antifungal Agents - pharmacology
Candida albicans
Candidiasis, Oral - drug therapy
Chemokines
Chemokines, CC - pharmacology
Mechanisms of Action: Physiological Effects
Mice
Microbial Sensitivity Tests
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Summary:is a commensal organism that causes life-threatening or life-altering opportunistic infections. Treatment of infections is limited by the paucity of antifungal drug classes. Naturally occurring antimicrobial peptides are promising agents for drug development. CCL28 is a CC chemokine that is abundant in saliva and has antimicrobial activity. In this study, we examine the killing capacity of CCL28 in oropharyngeal candidiasis as well as the spectrum and mechanism of anti- activity. In the mouse model of oropharyngeal candidiasis, application of wild-type CCL28 reduces oral fungal burden in severely immunodeficient mice without causing excessive inflammation or altering tissue neutrophil recruitment. CCL28 is effective against multiple clinical strains of Polyamine protein transporters are not required for CCL28 anti- activity. Both structured and unstructured CCL28 proteins show rapid and sustained fungicidal activity that is superior to that of clinical antifungal agents. Application of wild-type CCL28 to results in membrane disruption as measured by solute movement, enzyme leakage, and induction of negative Gaussian curvature on model membranes. Membrane disruption is reduced in CCL28 lacking the functional C-terminal tail. Our results strongly suggest that CCL28 can exert antifungal activity in part via membrane permeation and has potential for development as an anti- therapeutic agent without inflammatory side effects.
ISSN:0066-4804
1098-6596
DOI:10.1128/AAC.00210-20