Deciphering mechanisms of pathogenesis in candida glabrata: in the crossroad between drug resistance and virulence

Mafalda Banazol de Santa Rita Cavalheiro

Key information

Authors:

Mafalda Banazol de Santa Rita Cavalheiro (Mafalda Banazol de Santa Rita Cavalheiro)

Supervisors:

Miguel Nobre Parreira Cacho Teixeira (Miguel Nobre Parreira Cacho Teixeira)

Published in

10/12/2020

Abstract

In this thesis, the study of molecular mechanisms simultaneously involved in at least two of the three main processes for the survival of C. glabrata in the human host: biofilm formation, virulence and antifungal resistance; was pursued. This work presents two new regulators of biofilm formation, CgEfg1 and CgTec1, which together control 40% of all the transcriptomic changes happening in this complex process. In addition, biofilm formation was found to depend on unexpected players, like CgDtr1 and CgTpo4, which are key effectors of virulence in this pathogenic yeast, CgDtr1 as an acetate exporter whose action fights oxidative and acetic acid stress, while CgTpo4 is essential to resist the action of antimicrobial peptides and polyamines. Biofilm formation was also found to rely on the expression of two cell peripheral proteins, CgEpa3 and CgPil2, an adhesin and an eisosome component unraveled during the study of in vitro evolution towards azole resistance of a C. glabrata susceptible clinical isolate. CgEpa3 and CgPil2 are thus two effectors in azole resistance, the first believed to contribute to increased yeast aggregation, decreasing C. glabrata exposure to azole drugs, while CgPil2 contributes for lipid homeostasis at the plasma membrane, influencing the presence of MDR transporters involved in both antifungal resistance and biofilm formation.