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Fungal pathogens and their in vivo response in the context of antifungal tolerance and resistance

English title Fungal pathogens and their in vivo response in the context of antifungal tolerance and resistance
Applicant Sanglard Dominique
Number 172958
Funding scheme Project funding
Research institution Institut de Microbiologie - CHUV Faculté de Biologie et Médecine Université de Lausanne
Institution of higher education University of Lausanne - LA
Main discipline Medical Microbiology
Start/End 01.04.2017 - 30.11.2021
Approved amount 881'797.00
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Keywords (4)

Candida, anti fungal resistance and tolerance; Fungal virulence; Genomics, transcriptomics; antifungal resistance and tolerance

Lay Summary (French)

Lead
Les infections chez les humains causées par des agents pathogènes fongiques appartenant à des espèces de Candida (comme C. albicans et C. glabrata) restent une menace pour la santé humaine, et ceci même avec l'utilisation d'agents antifongiques disponibles. Il est donc important de comprendre comment les pathogènes fongiques répondent aux traitements médicamenteux, ce qui a été effectué au passé en conditions de laboratoire. Ce projet vise à comprendre la réponse médicamenteuse de ces deux agents pathogènes dans une nouvelle approche et dans le contexte des conditions qui sont celle de l’hôte.
Lay summary

Chez Candida albicans en premier lieu, ce projet abordera les mécanismes moléculaires responsables de la tolérance aux antifongiques et principalement aux azolés. La tolérance aux antifongiques reflète la capacité de Candida albicans à survivre à des agents antifongiques à des concentrations supérieures à celles requises pour inhiber la croissance. Nous aborderons la tolérance aux antifongiques en utilisant une combinaison d'approches génomiques et nous aborderons la pertinence de la tolérance par des expérimentations animales dans des conditions de traitements antifongiques.

Chez Candida glabrata ensuite, nous prévoyons de mieux comprendre la relation existant entre la réponse au médicament et l'augmentation de la virulence qui en résulte chez cette espèce de levure. Pour ce faire, ce projet utilisera non seulement les approches génomiques, mais utilisera également de nouvelles méthodes d'imagerie in vivo pour mieux comprendre comment Candida glabrata envahit les tissus et les organes de l'hôte.

Globalement, ce projet de recherche élargira nos connaissances sur les facteurs critiques pour Candida albicans et Candida glabrata pour la survie dans leurs hôtes et ouvrira une nouvelle compréhension de leur réponse sous pression antifongique in vivo. La modulation ciblée de ces facteurs peut aider à mieux contrôler les agents pathogènes fongiques chez leurs hôtes et peut réduire l'impact négatif des agents pathogènes fongiques sur la santé humaine.

Direct link to Lay Summary Last update: 13.07.2017

Lay Summary (English)

Lead
Infections in humans caused by fungal pathogens belonging to Candida species (such as C. albicans and C. glabrata) remain a threat to human health, even with the use of available antifungal agents. It is therefore important to understand how fungal pathogens respond to drug treatments, which has been performed in past in laboratory conditions. This project aims to understand drug response of these two pathogens in a novel approach within the context of host conditions.
Lay summary

In Candida albicans first, this project will address 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. We will approach antifungal tolerance using a combination of omic approaches and address the relevance of tolerance by in vivo antifungal treatment challenges.

 In Candida 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. In order to achieve this, this project will not only use omics approaches but will also use novel infection imaging methods to better understand how C. glabrata invade host tissues and organs.

Taken together, this research project will expand our knowledge on factors critical for both Candida albicans and Candida 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.

Direct link to Lay Summary Last update: 13.07.2017

Responsible applicant and co-applicants

Employees

Project partner

Publications

Publication
Investigating Candida glabrata Urinary Tract Infections (UTIs) in Mice Using Bioluminescence Imaging
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.
Participation of the ABC Transporter CDR1 in Azole Resistance of Candida lusitaniae
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.
Identification and Characterization of Mediators of Fluconazole Tolerance in Candida albicans
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.
Comparative Genomics for the Elucidation of Multidrug Resistance in Candida lusitaniae
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.

Collaboration

Group / person Country
Types of collaboration
Institut Pasteur France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof M. Sanguinetti (Rome) Italy (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Trends In Medical Mycology 2021 Poster Participation of the ABC Transporter CDR1 in Azole Resistance of Candida lusitaniae 28.09.2021 Aberdeen, Great Britain and Northern Ireland Sanglard Dominique;
Annual meeting Swiss Society of Infectious diseases 2021 Talk given at a conference Antifungal resistance: selected cases from the clinic and the environment 03.09.2021 Montreux, Switzerland Sanglard Dominique;
Annual meeting of the Swiss Society of Microbiology 2019 Poster Characterization of CRZ1, a positive mediator of antifungal tolerance in Candida albicans 03.09.2019 Zurich, Switzerland Trachsel Emilie;
Annual meeting of the Swiss Society of Microbiology 2019 Talk given at a conference In vivo imaging of Candida glabrata invasive infections in mice 03.09.2019 Zürich, Switzerland Schrevens Sanne;
Advanced Lecture Course Human Fungal Pathogens (HFP2019) Poster In vivo imaging of Candida glabrata invasive infections in mice 18.05.2019 La Colle-sur-Loup, France Sanglard Dominique; Schrevens Sanne;
Invited Institute Seminar Individual talk Understanding antifungal drug resistance and tolerance in fungal pathogens: impact of genomics 09.01.2019 Paris, France Sanglard Dominique;
Annual meeting of the French Society of Microbiology 2018 Talk given at a conference Mechanisms of antifungal resistance and tolerance in Candida spp. 01.10.2018 Paris, France Sanglard Dominique;
Annual Meeting of the Swiss Society of Microbiology 2018 Talk given at a conference Comparative genomics for understanding the development of multidrug resistance in Candida lusitaniae 28.09.2018 Lausanne, Switzerland Sanglard Dominique;
ISHAM 2018 Talk given at a conference Comparative genomics for understanding the development of multidrug resistance in Candida lusitaniae 30.06.2018 Amsterdam, Netherlands Sanglard Dominique;
ISHAM 2018 Poster Identification of mediators of antifungal tolerance in Candida albicans 30.06.2018 Amsterdam, Netherlands Delarze Eric;
14th Candida and Candidiasis meeting ASM Poster Identification of positive and negative mediators of antifungal tolerance in Candida albicans 15.04.2018 Rhode Island, United States of America Sanglard Dominique; Delarze Eric;
Invited Institute Seminar Individual talk A journey through fungal cell functions by antifungal drug resistance mechanisms 16.01.2018 Würzburg, Germany Sanglard Dominique;
Trends In Medical Mycology Talk given at a conference Understanding multidrug resistance in Candida lusitaniae 06.10.2017 Belgrade, Serbien Sanglard Dominique;
Invited Institute Seminar Innsbruck Individual talk Genomic approaches in the field of medical mycology: what can we learn? 30.05.2017 Innsbruck, Austria Sanglard Dominique;
Advanced Lecture Course Human Fungal Pathogens Talk given at a conference Identification of mediators of antifungal tolerance in Candida albicans 13.05.2017 La Colle-sur-Loup, France Sanglard Dominique; Delarze Eric;


Communication with the public

Communication Title Media Place Year
Media relations: print media, online media “Les champignons, des tueurs trop souvent ignorés” Allez Savoir Western Switzerland 2019
Media relations: print media, online media “Les champignons, une menace silencieuse sur la santé et l’alimentation humaine” Le Monde International 2018
Media relations: print media, online media Les Superchampignons », la nouvelle menace Le Matin Dimanche Western Switzerland 2018

Associated projects

Number Title Start Funding scheme
146936 Identification of factors associated with antifungal resistance and fitness/virulence in pathogenic Candida species 01.04.2013 Project funding
183376 Biocontained Confocal Microscopy Platform Lausanne University Hospital 01.10.2019 R'EQUIP
141848 Novel genome-wide transcriptomic approaches to challenge Candida albicans-hosts interactions 01.01.2013 Sinergia
173863 Multidisciplinary approaches to identify genetic determinants of Candida albicans pathogenicity 01.10.2017 Sinergia

Abstract

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.
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