Study of Innate Host Immune Response to C. Glabrata Clinical Isolates Resistant to Echinocandins: Impact on the Management of Candidemia in High-risk Patients

• Conditions: Candidemia of C. Glabrata

• Registration Number: NCT03652194
• Lead Sponsor: Centre Hospitalier Universitaire Dijon

Brief Summary

In the context of Candida yeast infections, a large number of studies have been published over the past two decades specifying the molecular mechanisms of antifungal resistance in different Candida species. However, few of these studies have explored how these mechanisms influence host immune response to this opportunistic pathogen. Recent advances in understanding how the host's immune system responds to Candida have initiated the emergence of a new research theme aimed at better understanding Candida's intrinsic and adaptive resistance mechanisms to antifungals can modulate "escape to" or "recognition by" the host's immune system. This knowledge could lead to (i) a better understanding of the predominance of certain Candida species with antifungal resistance in certain patient populations, (ii) a better understanding of why high levels of in vitro resistance are not necessarily correlated with in vivo therapeutic failure, and (iii) effective immunotherapeutic strategies to control Candida resistance to antifungals.

It is therefore crucial to investigate the impact of Candida's resistance to antifungals on the host's innate immune response. Indeed, most antifungal resistance mechanisms have a direct or indirect structural modification of the fungal wall. However, it is the composition of this wall that is involved in the recognition of Candida by the host cell via the pattern recognition receptors (PRRs). We therefore put forward the very probable hypothesis that changes in the fungal wall, induced by the appearance of resistance, could alter the recognition of Candida by PRRs and thus trigger a different immune response, either qualitatively (type of cytokines secreted) or quantitatively (amplitude and duration of the immune response). However, even if initial experimental data support the hypothesis of a possible link between resistance and a modulation of the innate immune response in digestive mucosa (the most frequent starting point for disseminated candidiasis), many questions remain regarding (i) the proteins and mechanisms of the modulated immune cascade, (ii) the modification of the immune response according to the Candida species in question and (iii) the modification of the immune response according to the resistance phenotype in question.

Detailed Description

Not available

Study Timeline

• Study Start: 2018-01-01
• Status Verified: 2018-08
• Study First Submitted: 2018-08-28
• Study First Submitted QC: 2018-08-28
• Last Update Submitted: 2018-08-28
• Study First Posted: 2018-08-29
• Last Update Posted: 2018-08-29
• Primary Completion: 2019-01
• Study Completion: 2019-06

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 21

Inclusion Criteria

• 10 clinical isolates sensitive to all antifungal agents
• 10 echinocandin-resistant clinical isolates (Eucast, caspofungin > 8µg/ml)

Clinical strains of C. glabrata susceptible or resistant to echinocandins will be selected on selected criteria:

• patient's immune status
• therapeutic management
• clinical developments

Exclusion Criteria

• Not applicable

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Test SytoxOrange	Baseline	In vitro study of different cytotoxicity markers in digestive epithelial cells
Quantification of the gene expression of the various cytokines associated with the immune response in digestive epithelial cells.	Baseline
Quantification of accession and invasion	Baseline	In vitro study of different virulence markers

Trial Locations

Locations (1)

Chu Dijon Bourogne; 🇫🇷 Dijon, France