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Chemokine CCL28 Is a Potent Therapeutic Agent for Oropharyngeal Candidiasis
Jie He1, Monica A Thomas2, Jaime de Anda3
1Department of Pediatrics, Division of Infectious Disease, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Abstract:
Candida albicans is a commensal organism that causes life-threatening or life-altering opportunistic infections. Treatment of Candida 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 in vitro antimicrobial activity. In this study, we examine the in vivo Candida killing capacity of CCL28 in oropharyngeal candidiasis as well as the spectrum and mechanism of anti-Candida 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 C. albicans Polyamine protein transporters are not required for CCL28 anti-Candida 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 C. albicans 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-Candida therapeutic agent without inflammatory side effects.
Insights
The antimicrobial peptide CCL28 effectively reduces Candida albicans fungal burden in mice. This chemokine shows potent, rapid fungicidal activity by disrupting fungal membranes, offering a promising therapeutic candidate for candidiasis.
Area of Science:
- Microbiology
- Immunology
- Drug Discovery
Background:
- Candida albicans causes opportunistic infections, with limited treatment options due to few antifungal drug classes.
- Naturally occurring antimicrobial peptides are potential candidates for novel antifungal drug development.
- CCL28, a CC chemokine found in saliva, exhibits in vitro antimicrobial activity.
Purpose of the Study:
- To investigate the in vivo Candida-killing capacity of CCL28 in oropharyngeal candidiasis.
- To determine the spectrum and mechanism of CCL28's anti-Candida activity.
- To evaluate CCL28's potential as a therapeutic agent for Candida infections.
Main Methods:
- Utilized a mouse model of oropharyngeal candidiasis to assess CCL28's efficacy.
- Examined the anti-Candida activity spectrum against multiple clinical strains of C. albicans.
- Investigated the mechanism of action, including membrane disruption and polyamine transporter involvement.
- Assessed inflammatory responses and neutrophil recruitment in treated mice.
Main Results:
- Wild-type CCL28 significantly reduced oral fungal burden in immunodeficient mice without increasing inflammation.
- CCL28 demonstrated rapid and sustained fungicidal activity against multiple C. albicans strains, outperforming clinical antifungals.
- CCL28 induced membrane disruption in C. albicans, evidenced by solute movement and enzyme leakage.
- Antifungal activity was linked to membrane permeation, particularly involving the C-terminal tail of CCL28.
Conclusions:
- CCL28 exhibits potent in vivo antifungal activity against Candida albicans.
- The mechanism of action involves disruption of the fungal cell membrane.
- CCL28 holds potential as a therapeutic agent for candidiasis with minimal inflammatory side effects.
