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Novel genome-wide transcriptomic approaches to challenge Candida albicans-hosts interactions

Applicant Sanglard Dominique
Number 141848
Funding scheme Sinergia
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 01.01.2013 - 31.12.2016
Approved amount 1'188'732.00
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Keywords (4)

High throughput sequencing; Candida; innate immunity; virulence

Lay Summary (English)

Lead
Lay summary

Novel genome-wide transcriptomic approaches to challenge Candida albicans-hosts interactions

Aims of the project

This project aims to use several genomic approaches in order to discover novel cellular factors involved in the interaction of the human pathogen Candida albicans with cells of the host. The project is composed of three different complementary research partners, each of which will contribute to different aspects of the project. The first two partners (D. Sanglard, University of Lausanne and University Hospital Center, CHUV,  and S. Leibundgut, ETHZ) will contribute to the understanding of fungal and host factors in the fungal-host interactions, respectively. The third partner (M. Pagni, University of Lausanne) will be associated with the genomic data analysis and development of bioinformatic tools.

Background

The occurrence of infections with the yeast Candida albicans in patients with deficiencies in their immune system is still associated an important clinical problem with a high mortality. Antifungal therapies exist, however their efficiency is limited, which therefore necessitate the identification of novel antifungal molecules. The interactions of C. albicans with its host are complex and depend on both fungal and host -derived factors. The fungal factors that are critical for the maintenance of C. albicans within the host could constitute novel source of targets for new antifungals. Transcription factors (TF), which control the expression of gene targets and coordinate the response of C. albicans in its interaction with the host, play an important role for C. albicans persistence in the host.

Methods and saignificance

In this research proposal, in order to identify novel transcription factors important for the interaction of C. albicans with its host, we plan to use high throughput RNA sequencing  (HTRS) technologies to probe the gene expression profiles from the host and the fungus interacting with each other.

Partner 1 (D. Sanglard) has identified novel C. albicans TFs required for host interactions. Mutants for these TFs display an enhanced or attenuated infectivity, respectively, when tested in a systemic mouse infection model. Here, Partner 1 aims at functionally characterizing the target genes of these TFs and their regulation during infection by using HTRS.

Partner 2 (S. LeibundGut-Landmann) will investigate the host response to C. albicans in order to identify specific immune mechanisms that are affected by the TF mutants. For this, several assays with mouse cells cells will be combined with HTRS analyses.

Partner 3 (M. Pagni) will use HTRS to probe both the fungal and host genes expression profiles with the goal to identify novel host response pathway that contribute to C. albicans control in the host.  

The results obtained from this project will advance our current understanding of the intimate crosstalk between the fungus and its host and will open up new opportunities for the future development of novel therapies.  

 


Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
IL-1 coordinates the neutrophil response to C. albicans in the oral mucosa
Altmeier S., Toska A., Teijeira A., Halin C., LeibundGut-Landmann S. (2016), IL-1 coordinates the neutrophil response to C. albicans in the oral mucosa, in PLoS Pathogens, 12(9), e1005882.
Examining the virulence of Candida albicans transcription factor mutants using Galleria mellonella and mouse infection models
Amorim-Vaz Sara, Delarze Eric, Ischer Françoise, Sanglard Dominique, Coste Alix T. (2015), Examining the virulence of Candida albicans transcription factor mutants using Galleria mellonella and mouse infection models, in Frontiers in Microbiology, 06, 1-14.
Novel Approaches for Fungal Transcriptomics from Host Samples.
Amorim-Vaz Sara, Sanglard Dominique (2015), Novel Approaches for Fungal Transcriptomics from Host Samples., in Frontiers in microbiology, 6, 1571-1571.
RNA Enrichment Method for Quantitative Transcriptional Analysis of Pathogens In Vivo Applied to the Fungus Candida albicans.
Amorim-Vaz Sara, Tran Van Du T, Pradervand Sylvain, Pagni Marco, Coste Alix T, Sanglard Dominique (2015), RNA Enrichment Method for Quantitative Transcriptional Analysis of Pathogens In Vivo Applied to the Fungus Candida albicans., in mBio, 6(5), 00942-15.
Animal Models to Study Fungal Virulence and Antifungal Drugs
Alix T. Coste and S. Amorim-Vaz, Animal Models to Study Fungal Virulence and Antifungal Drugs, in Alix T. Coste and Patrick Vandeputte (ed.), Caister Academic Press, UK.
Immunity to Fungal Infections
Altmeier S., LeibundGut-Landmann S., Immunity to Fungal Infections, in Agostinho Carvalho (ed.), Springer, 2016.

Collaboration

Group / person Country
Types of collaboration
Prof. B. Hube, HKI Jena Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
74th Annual Meeting of the Swiss Society for Microbiology Talk given at a conference Transcriptomic approach to determine the interaction between Candida albicans and the host mucosa in vivo 13.06.2016 Bern, Switzerland Altmeier Simon; Pagni Marco; Leibundgut-Landmann Salomé; Martins Amorim Vaz Sara; Sanglard Dominique;
Candida and Candidiasis, ASM Talk given at a conference Characterization of a new virulence gene in Candida albicans 13.04.2016 Seattle, United States of America Martins Amorim Vaz Sara; Sanglard Dominique;
73rd Annual Meeting and Assembly of the Swiss Society of Microbiology Talk given at a conference Transcriptional profiles of Candida albicans during systemic infection of two host organisms 27.05.2015 Lugano, Switzerland Tran Thuong Van Du; Pagni Marco; Sanglard Dominique; Martins Amorim Vaz Sara;
73rd Annual Meeting and Assembly of the Swiss Society of Microbiology Talk given at a conference Transcriptional profiles of Candida albicans during systemic infection of two host organisms 27.05.2015 Lugano, Switzerland Martins Amorim Vaz Sara; Sanglard Dominique;
Sixth FEBS Advanced Lecture Course Human Fungal Pathogens: Molecular Mechanisms of Host-Pathogen Interactions and Virulence Poster Transcriptomic profiles of Candida albicans in systemic infection of two host organisms 16.05.2015 La Colle sur Loup, France Pagni Marco; Tran Thuong Van Du; Martins Amorim Vaz Sara; Sanglard Dominique;
6th FEBS Advanced Lecture Course on Human Fungal Pathogens Talk given at a conference The role of non-hematopoietic cells in protective immunity against C. albicans 15.05.2015 La Colle-sur-Loup, France Altmeier Simon; Leibundgut-Landmann Salomé;
International Society for Human and Animal Mycology (ISHAM) Talk given at a conference Transcriptomic profiles of Candida albicans in systemic infection of two host organisms 03.05.2015 Melbourne, Australia Sanglard Dominique;
SGM Focused Meeting 2014: Infection Models to Investigate Microbial Disease and Antimicrobial Therapies Talk given at a conference Large-scale evaluation of Galleria mellonella as a model to study Candida albicans virulence factors 17.11.2014 London, Great Britain and Northern Ireland Sanglard Dominique; Martins Amorim Vaz Sara;
SGM Focused Meeting 2014: Infection Models to Investigate Microbial Disease and Antimicrobial Therapies Talk given at a conference Large-scale evaluation of Galleria mellonella as a model to study Candida albicans virulence factors 17.11.2014 Londres, Great Britain and Northern Ireland Martins Amorim Vaz Sara;
6th Student Retreat of the Microbiology and Immunology Program Talk given at a conference The role of the oral epithelium in protective immunity against C. albicans 12.09.2014 Locarno, Switzerland Leibundgut-Landmann Salomé; Altmeier Simon;
D-BIOL Symposium Individual talk Host-Fungal Interactions at the Host Epithelium 10.06.2014 Davos, Switzerland Martins Amorim Vaz Sara; Altmeier Simon; Sanglard Dominique; Leibundgut-Landmann Salomé;
12th ASM Conference on Candida and Candidiasis Talk given at a conference “Mini-host and mouse infection models for probing virulence of Candida albicans transcription factor mutants 26.03.2014 New Orleans, United States of America Martins Amorim Vaz Sara; Sanglard Dominique;
Department Research Day Talk given at a conference Mini-host and mouse infection models for probing virulence of Candida albicans transcription factors mutants 11.12.2013 Lausanne, Switzerland Sanglard Dominique; Martins Amorim Vaz Sara;


Associated projects

Number Title Start Funding scheme
139605 Genome wide analysis of the role of transcription factors of Candida albicans in the survival in host conditions 01.06.2012 Marie Heim-Voegtlin grants
173863 Multidisciplinary approaches to identify genetic determinants of Candida albicans pathogenicity 01.10.2017 Sinergia
166206 Tissue-specific host defense mechanisms against Candida albicans 01.10.2016 Project funding
173863 Multidisciplinary approaches to identify genetic determinants of Candida albicans pathogenicity 01.10.2017 Sinergia
146936 Identification of factors associated with antifungal resistance and fitness/virulence in pathogenic Candida species 01.04.2013 Project funding
172958 Fungal pathogens and their in vivo response in the context of antifungal tolerance and resistance 01.04.2017 Project funding
123342 Host defense against fungal infections 01.01.2010 SNSF Professorships

Abstract

The occurrence of Candida albicans infections in immunocompromized patients is still associated with a high mortality rate even though antifungal therapies are administered. The interactions of C. albicans with its host are complex and depend on both fungal and host -derived factors. Novel drug targets could emerge from the identification of new fungal molecules that are critical for the maintenance of the fungus in the host as well as from new host response factors. In recent years, several factors critical for fungal virulence have been identified. Among them are transcription factors (TFs), which coordinate the fungal response in adaptation to the host environment and thus play an important role for C. albicans persistence in the host. In this research proposal, we plan to use genome-wide approaches for the identification of novel transcription factors with this function and for mapping the host response to C. albicans. Novel high throughput sequencing technologies now allow the simultaneous generation of gene expression profiles from the host and the fungus interacting with each other. The successful completion of this project will depend on the expertise of three independent research groups with complementary interests. Partner 1 (D. Sanglard) has previously identified novel C. albicans-derived TFs involved in host tissue colonization. Mutants for these TFs display an enhanced or attenuated infectivity, respectively, when tested in a systemic mouse infection model. Here, Partner 1 aims at functionally characterizing the target genes of these TFs and their regulation during infection by using RNA-seq and ChIP seq technologies. Partner 2 (S. LeibundGut-Landmann) will investigate the host response to C. albicans in order to identify specific immune mechanisms that are affected by the TF mutants. For this, cell culture assays and mouse infection experiments using a model for oropharyngeal candidiasis will be combined with RNA-seq analyses. Partner 3 (M. Pagni) will use RNA-seq technologies to probe both the fungal and host transcriptomes with the goal to identify novel host response pathway that contribute to C. albicans control. Associated to Partners 1 and 2, Partner 3 will perform the collection and data mining of the transcriptional data. He will use the transcriptional data not only for the development of efficient new data analysis tools but also for the identification of metabolic pathways specifically regulated by C. albicans during the host infection process. In conclusion, this proposal maximizes the partnership of three different research groups in order to characterize in-depth the function of novel TFs specifically involved the C.albicans-host interaction. The results obtained from this project will advance our current understanding of the intimate crosstalk between the fungus and its host and will open up new opportunities for the future development of novel therapies.
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