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Published on: February 14, 2018
Effects of antifungal interventions on the outcome of experimental infections with phenotypic switch variants of
Bettina C Fries1, Emily Cook, Xiabo Wang
1Department of Medicine, Albert Einstein College of Medicine, Golding 702, 1300 Morris Park Ave., Bronx, New York 10461, USA. fries@aecom.yu.edu
Abstract:
In cryptococcal infection, phenotypic switching from a smooth to a mucoid variant can occur in vivo, producing variants with enhanced virulence that are subsequently selected and affect the outcome of infection. Here, we demonstrate that antifungal treatment of the chronically infected host can promote this phenomenon. Amphotericin B treatment reduces fungal burden less effectively in mucoid variant-infected than in smooth variant-infected mice. Consequently, amphotericin B treatment resulted in a more pronounced prolongation of survival in smooth variant-infected than in mucoid variant-infected mice (20 versus 42 days; P < 0.05). Administration of anticapsular monoclonal antibody mediated better protection in smooth variant-infected than in mucoid variant-infected mice, although a protective effect was not consistently observed at all doses. Most interestingly, both antifungal drug therapy and administration of anticapsular monoclonal antibody promoted the selection of mucoid variants in smooth variant-infected mice, a phenomenon manifested by a statistically higher percentage of mucoid colonies in smooth variant-infected mice than in nontreated control mice. This finding suggests that both chemotherapeutic and immunological antifungal interventions may promote the selection of the more virulent mucoid variant, which could affect the outcome of infection in chronically infected hosts.
Insights
Antifungal treatments can unexpectedly promote the selection of more virulent mucoid variants in cryptococcal infections. This suggests that both drug and antibody therapies may impact infection outcomes in chronically infected hosts.
Area of Science:
- Mycology
- Infectious Diseases
- Immunology
Background:
- Cryptococcal infection involves phenotypic switching from smooth to mucoid variants, with mucoid variants exhibiting enhanced virulence.
- This switching can occur in vivo and influence infection outcomes.
- The effect of antifungal interventions on this phenotypic switch is not fully understood.
Purpose of the Study:
- To investigate whether antifungal treatment promotes the in vivo selection of the more virulent mucoid variant of Cryptococcus.
- To assess the impact of antifungal drug therapy and anticapsular monoclonal antibody administration on cryptococcal variant selection and infection outcomes.
Main Methods:
- Mice with chronic cryptococcal infection were treated with amphotericin B or anticapsular monoclonal antibody.
- Fungal burden and survival rates were compared between mice infected with smooth versus mucoid variants.
- The percentage of mucoid colonies was quantified in treated and control groups.
Main Results:
- Amphotericin B was less effective in reducing fungal burden in mucoid variant-infected mice.
- Antifungal treatment and anticapsular monoclonal antibody administration promoted the selection of mucoid variants in smooth variant-infected mice.
- Both interventions led to a statistically significant increase in mucoid colonies compared to controls.
Conclusions:
- Antifungal chemotherapeutic and immunological interventions may inadvertently promote the selection of the more virulent mucoid variant in cryptococcal infections.
- This selection phenomenon could significantly affect the clinical outcome of infections in chronically infected hosts.
- Further research is needed to understand and mitigate this treatment-induced variant selection.
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