Hyperexpression of CDRs and HWP1 genes negatively impacts on Candida albicans virulence.

Bruno Maras,Letizia Angiolella,Maria D’Erme,Giuseppina Mignogna,Anna Maggiore,Aijaz Ahmad

doi:10.1371/journal.pone.0252555

Abstract

C. albicans is a commensal organism present in the human microbiome of more than 60% of the healthy population. Transition from commensalism to invasive candidiasis may occur after a local or a general failure of host's immune system. This transition to a more virulent phenotype may reside either on the capacity to form hyphae or on an acquired resistance to antifungal drugs. Indeed, overexpression of genes coding drug efflux pumps or adhesins, cell wall proteins facilitating the contact between the fungus and the host, usually marks the virulence profile of invasive Candida spp. In this paper, we compare virulence of two clinical isolates of C. albicans with that of laboratory-induced resistant strains by challenging G. mellonella larvae with these pathogens along with monitoring transcriptional profiles of drug efflux pumps genes CDR1, CDR2, MDR1 and the adhesin genes ALS1 and HWP1. Although both clinical isolates were found resistant to both fluconazole and micafungin they were found less virulent than laboratory-induced resistant strains. An unexpected behavior emerged for the former clinical isolate in which three genes, CDR1, CDR2 and HWP1, usually correlated with virulence, although hyperexpressed, conferred a less aggressive phenotype. On the contrary, in the other isolate, we observed a decreased expression of CDR1, CDR2 and HWP1as well as of MDR1 and ALS1 that may be consistent with the less aggressive performance observed in this strain. These altered gene expressions might directly influence Candida virulence or they might be an epiphenomenon of a vaster rearrangement occurred in these strains during the challenge with the host's environment. An in-deepth comprehension of this scenario could be crucial for developing interventions able to counteract C. albicans invasiveness and lethality.

Highlights

In this paper we compare the virulence and lethality of two clinical isolates with those of three laboratory-induced resistant (LIR) strains to fluconazole or micafungin or both, by challenging G. mellonella larvae with these pathogens along with monitoring transcriptional profiles of CDR1, CDR2, MDR, ALS1 and HWP1 genes
We examined genes frequently associated with increased fungal pathogenic profiles as those codifying for multidrug efflux pumps involved in drug resistance or adhesins, cell wall proteins necessary for fungal colonization
The formers were less aggressive than LIRs especially when compared with the double LIR strain

Summary

Introduction

Hyperexpression of CDRs and HWP1 impacts on Candida albicans virulence https://wwwuniroma1.it The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The transition to hyphal form and adherence cause damage to the host mucosa by the combined action of secreted aspartyl proteases and phospholipases thereby facilitating the invasion of the organism into the epithelium [8,9] In both commensal and pathogenic lifestyles, C. albicans utilizes a set of proteins called adhesins to prime adherence among C. albicans cells, between C. albicans and host cells or with inanimate surfaces. In this paper we compare the virulence and lethality of two clinical isolates with those of three laboratory-induced resistant (LIR) strains to fluconazole or micafungin or both, by challenging G. mellonella larvae with these pathogens along with monitoring transcriptional profiles of CDR1, CDR2, MDR, ALS1 and HWP1 genes This approach may gain insight on the relathionship existing between these molecular factors and virulence in organisms either isolated from human host or developed as coltured strains

Materials and methods

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Discussion