Candida, anti fungal resistance and tolerance; Fungal virulence; Genomics, transcriptomics; antifungal resistance and tolerance
Schrevens Sanne, Sanglard Dominique (2021), Investigating Candida glabrata Urinary Tract Infections (UTIs) in Mice Using Bioluminescence Imaging, in Journal of Fungi
, 7(10), 844-844.
Borgeat Valentin, Brandalise Danielle, Grenouillet Frédéric, Sanglard Dominique (2021), Participation of the ABC Transporter CDR1 in Azole Resistance of Candida lusitaniae, in Journal of Fungi
, 7(9), 760-760.
Delarze Eric, Brandt Ludivine, Trachsel Emilie, Patxot Marion, Pralong Claire, Maranzano Fabio, Chauvel Murielle, Legrand Mélanie, Znaidi Sadri, Bougnoux Marie-Elisabeth, d’Enfert Christophe, Sanglard Dominique (2020), Identification and Characterization of Mediators of Fluconazole Tolerance in Candida albicans, in Frontiers in Microbiology
, 11, 1-19.
Kannan Abhilash, Asner Sandra A., Trachsel Emilie, Kelly Steve, Parker Josie, Sanglard Dominique (2019), Comparative Genomics for the Elucidation of Multidrug Resistance in Candida lusitaniae, in mBio
, 10(6), 1.
Fungal pathogens including Candida albicans and Candida glabrata are the two most common Candida species causing fungal diseases in human. These diseases are still causing high mortality (30-60%) among hospitalized patients. This suggests that, even if several antifungal agents are used to treat these infections, their efficacy remains limited. Not only it is important to identify additional factors enabling the survival of fungal pathogens in their hosts for better counteractions, but is it also necessary to better understand how fungal pathogens respond to drugs within their hosts in order to target critical responsive genes. The current proposal is aimed to answer these questions both in C. albicans and C. glabrata that are pathogens with whom we acquired significant knowledge over the past years.In C. albicans first, we plan to investigate the molecular mechanisms responsible for tolerance to antifungal drugs and principally to azoles. Antifungal tolerance reflects the ability of C. albicans to survive to antifungal agents at concentrations higher than those required to inhibit growth. On one hand, it is still not totally clear whether antifungal tolerance impacts on drug efficacy and, on the other hand, mechanisms of antifungal tolerance are still poorly understood. We will approach here these two important questions 1) by using a set of clinical strains with known azole tolerance profiles; 2) by deciphering genomic and transcriptional data in these strains to identify mediators of tolerance; 3) by testing the relevance of antifungal tolerance in animal models of infection; 4) in addition, and in order to better understand the response of C. albicans to antifungal treatments in the host, we will probe transcriptomes in vivo under antifungal (azole) pressure. This task is now feasible with state-of-the-art RNA enrichment technologies implemented in our laboratory. These approaches are likely to result in the identification of genes involved in azole tolerance and that are specifically regulated in vivo by C. albicans in the presence of antifungal agents to facilitate the survival of this pathogen in the host.In C. glabrata next, we plan to further understand the relationship existing between the drug response and the resulting increase of fitness and virulence existing in this yeast species. We have accumulated several lines of evidence in the past that C. glabrata isolates acquiring azole resistance have increased capacity to adhere (via adhesins) to host cells, which helps to establish robust infections. With similar in vivo transcriptomics approaches used in C. albicans, we will here: 1) undertake the detailed transcriptional profile of C. glabrata in vivo with and without azole exposure in order to scrutinize genes expressed in vivo (especially adhesins) differentially expressed under drug pressure. Since C. glabrata is haploid, we will also: 2) use the power of a novel transposon mutagenesis tool to produce high coverage mutant libraries on specific C. glabrata clinical isolates, which has not been yet undertaken. The produced libraries will be useful to identify adherence mediators that are important for C. glabrata in contact with host cells and serving C. glabrata to establish efficient infections in the host.Taken together, this research project will expand our knowledge on factors critical for both C. albicans and C. glabrata for survival in their hosts and will open novel understanding on their response under antifungal pressure in vivo. The targeted modulation of these factors may help a better control of fungal pathogens in their hosts and may reduce the negative impact of fungal pathogens on human health.