Rhesus Theta Defensin 1 Promotes Long Term Survival in Systemic Candidiasis by Host Directed Mechanisms

Virginia Basso, Dat Q. Tran, Justin B. Schaal, Patti Tran, Yoshihiro Eriguchi, Diana Ngole, Anthony E. Cabebe, A. young Park, Paul M. Beringer, André J. Ouellette, Michael E. Selsted

Research output: Contribution to journalArticle

Abstract

Invasive candidiasis is an increasingly frequent cause of serious and often fatal infections in hospitalized and immunosuppressed patients. Mortality rates associated with these infections have risen sharply due to the emergence of multidrug resistant (MDR) strains of C. albicans and other Candida spp., highlighting the urgent need of new antifungal therapies. Rhesus theta (θ) defensin-1 (RTD-1), a natural macrocyclic antimicrobial peptide, was recently shown to be rapidly fungicidal against clinical isolates of MDR C. albicans in vitro. Here we found that RTD-1 was rapidly fungicidal against blastospores of fluconazole/caspofungin resistant C. albicans strains, and was active against established C. albicans biofilms in vitro. In vivo, systemic administration of RTD-1, initiated at the time of infection or 24 h post-infection, promoted long term survival in candidemic mice whether infected with drug-sensitive or MDR strains of C. albicans. RTD-1 induced an early (4 h post treatment) increase in neutrophils in naive and infected mice. In vivo efficacy was associated with fungal clearance, restoration of dysregulated inflammatory cytokines including TNF-α, IL-1β, IL-6, IL-10, and IL-17, and homeostatic reduction in numbers of circulating neutrophils and monocytes. Because these effects occurred using peptide doses that produced maximal plasma concentrations (Cmax) of less than 1% of RTD-1 levels required for in vitro antifungal activity in 50% mouse serum, while inducing a transient neutrophilia, we suggest that RTD-1 mediates its antifungal effects in vivo by host directed mechanisms rather than direct fungicidal activity. Results of this study suggest that θ-defensins represent a new class of host-directed compounds for treatment of disseminated candidiasis.

Original languageEnglish
Article number16905
JournalScientific reports
Volume9
Issue number1
DOIs
Publication statusPublished - Dec 1 2019
Externally publishedYes

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Survival
Infection
caspofungin
Neutrophils
Invasive Candidiasis
Defensins
Peptides
Interleukin-17
Fluconazole
Candidiasis
Biofilms
Candida albicans
Interleukin-1
Interleukin-10
Systemic candidiasis
theta-defensin
Monocytes
Interleukin-6
Cytokines
Mortality

All Science Journal Classification (ASJC) codes

  • General

Cite this

Rhesus Theta Defensin 1 Promotes Long Term Survival in Systemic Candidiasis by Host Directed Mechanisms. / Basso, Virginia; Tran, Dat Q.; Schaal, Justin B.; Tran, Patti; Eriguchi, Yoshihiro; Ngole, Diana; Cabebe, Anthony E.; Park, A. young; Beringer, Paul M.; Ouellette, André J.; Selsted, Michael E.

In: Scientific reports, Vol. 9, No. 1, 16905, 01.12.2019.

Research output: Contribution to journalArticle

Basso, V, Tran, DQ, Schaal, JB, Tran, P, Eriguchi, Y, Ngole, D, Cabebe, AE, Park, AY, Beringer, PM, Ouellette, AJ & Selsted, ME 2019, 'Rhesus Theta Defensin 1 Promotes Long Term Survival in Systemic Candidiasis by Host Directed Mechanisms', Scientific reports, vol. 9, no. 1, 16905. https://doi.org/10.1038/s41598-019-53402-z
Basso, Virginia ; Tran, Dat Q. ; Schaal, Justin B. ; Tran, Patti ; Eriguchi, Yoshihiro ; Ngole, Diana ; Cabebe, Anthony E. ; Park, A. young ; Beringer, Paul M. ; Ouellette, André J. ; Selsted, Michael E. / Rhesus Theta Defensin 1 Promotes Long Term Survival in Systemic Candidiasis by Host Directed Mechanisms. In: Scientific reports. 2019 ; Vol. 9, No. 1.
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