A subdose of fluconazole alters the virulence ofCryptococcus gattiiduring murine cryptococcosis and modulates type I interferon expression

Abstract

Cryptococcosis is an invasive infection caused by yeast-like fungus of the genera Cryptococcus spp. The antifungal therapy for this disease provides some toxicity and the incidence of infections caused by resistant strains increased. Thus, we aimed to assess the consequences of fluconazole subdoses during the treatment of cryptococcosis in the murine inflammatory response and in the virulence factors of Cryptococcus gattii. Mice infected with Cryptococcus gattii were treated with subdoses of fluconazole. We determined the behavior of mice and type 1 interferon expression during the treatment; we also studied the virulence factors and susceptibility to fluconazole for the colonies recovered from the animals. A subdose of fluconazole prolonged the survival of mice, but the morbidity of cryptococcosis was higher in treated animals. These data were linked to the increase in: (i) fluconazole minimum inhibitory concentration, (ii) capsule size and (iii) melanization of C. gattii, which probably led to the increased expression of type I interferons in the brains of mice but not in the lungs. In conclusion, a subdose of fluconazole altered fungal virulence factors and susceptibility to this azole, leading to an altered inflammatory host response and increased morbidity.

Host-Pathogen Interactions Mediated by MDR Transporters in Fungi: As Pleiotropic as it Gets!

“…Cryptococcus gattii seems to count with drug transporters for its full virulence in the brain and the pulmonary tissue, like the MFS Mdr1 and the ABC Pdr11 transporters, determinants of C. gattii MDR [ 58 , 114 ]. The MDR1 gene was found to be upregulated in cells recovered from the brain and lungs of infected mice, while PDR11 was overexpressed in cells recovered from the lungs of infected mice [ 151 ]. Both Mdr1 and Pdr11 were proposed to play an additional role C. gattii virulence and adaptation to the host environment, although the exact mechanism underlying this observation is unclear.…”

Fungal Pathogenesis in Humans

“…Cryptococcus gattii seems to count with drug transporters for its full virulence in the brain and the pulmonary tissue, like the MFS Mdr1 and the ABC Pdr11 transporters, determinants of C. gattii MDR [58,114]. The MDR1 gene was found to be upregulated in cells recovered from the brain and lungs of infected mice, while PDR11 was overexpressed in cells recovered from the lungs of infected mice [151]. Both Mdr1 and Pdr11 were proposed to play an additional role C. gattii virulence and adaptation to the host environment, although the exact mechanism underlying this observation is unclear.…”

Antifungal Resistance, Metabolic Routes as Drug Targets, and New Antifungal Agents: An Overview about Endemic Dimorphic Fungi

“…In this case, the azole tolerance is the result of CBC repression that increases sterol synthesis. In Cryptococcus neoformans , the exposure of infected mice to a low dose of fluconazole increases the minimum inhibitory concentration (MIC) of colonies recovered from animals and increases the melanization and capsule size, which are classical virulence factors in this fungus, showing that previous exposure to antifungals leads to different resistance mechanisms in different fungal species [14]. The degradation of azoles is not well characterized, but studies performed with A. fumigatus correlate the mitochondrial complex I with metabolism of azoles, causing drug resistances, as mutants of this complex lost azole resistance [15].…”