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Identifier

000381277

Title

Διερεύνηση της επίδρασης υποανασταλτικών συγκεντρώσεων τριαζολών στην παθογονικότητα ζυγομηκύτων

Alternative Title

The effects of voriconazole exposure on zygomycetes virulence

Author

Λάμαρης, Γρηγόρης Α

Thesis advisor

Σαμώνης, Γ.

Reviewer

Σαββάκης, Χ.
Μαυρουδής, Δ.

Abstract

Background. Breakthrough zygomycosis is increasingly reported in high-risk immunosupressed patients receiving voriconazole (VRC) prophylaxis, reflecting either selective pressure or voriconazole-associated alterations in Zygomycetes virulence. We tested the latter hypothesis using two phylogenetically disparate animal models of zygomycosis. Animals and Methods. Three clinical Zygomycetes isolates and one Aspergillus fumigatus reference isolate were exposed to VRC by serial passages on medium containing sub-inhibitory concentrations of VRC or other antifungals used as controls. The virulence of VRC-exposed Zygomycetes was compared with that of non VRC-exposed isolates in wild type as well as Toll deficient Drosophila melanogaster fruit flies by assessing differences in survival following infection. The virulence of VRC-exposed Rhizopus oryzae conidia was compared with that of non VRC-exposed conidia in immunosupressed Balb-C mice by assessing survival curves, pulmonary fungal burdens, and the expression of inflammation-associated genes following infection. Results. Exposure of Zygomycetes isolates to VRC but not to itraconazole, amphotericin B, or caspofungin resulted in significantly decreased survival rates in Toll-deficient and wild-type fruit flies. VRC exposure did not alter the virulence of the Aspergillus fumigatus isolate Af293 in Toll-deficient flies. In the murine model, infection with a Rhizopus oryzae isolate pre-exposed to VRC was associated with decreased survival rates and increased pulmonary fungal burden compared with the unexposed isolate. In addition, enhanced angioinvasion, inflammation and expression of genes involved in stress response and tissue repair were found in mouse lungs infected with VRC-exposed R. oryzae. Conclusions. Exposure of Zygomycetes to VRC selectively enhances their virulence in two phylogenetically disparate animal models of zygomycosis using fruit flies and immunosupressed Balb-C mice. The mechanisms underlying these phenotypic changes should be studied further.

Language

Greek

Subject

Fungal infection

Rhizopus

Voriconazole

Zygomycetes

Zygomycosis

Βορικοναζόλη

Ζυγομήκυτες

Ζυγομηκυτίαση

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