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

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.

Study Overview

• Status: Unknown
• Conditions: Candidemia of C. Glabrata
• Intervention / Treatment: Other: in vitro evaluation of epithelial immune response during C. glabrata infection; Other: study of the impact of resistance phenotype acquisition on the virulence of C. glabrata isolates

• Study Type: Observational
• Enrollment (Actual): 21

Contacts and Locations

Study Locations

• France
  • Dijon, France, 21000
    • Chu Dijon Bourogne

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Collection from the "multicentric study of Echinocandin-resistance in Candida glabrata candidemia" (multicentre retrospective study on a cohort of 172 patients managed for a C. glabrata cadidemia between 2013 and 2015).

Description

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 Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Reference strain ATCC; 1 strain sensitive to all antifungals	Other: in vitro evaluation of epithelial immune response during C. glabrata infection; study of the expression of genes coding for different proteins involved in the RTqPCR activation cascade; study of protein expression by the Western-Blot method; Other: study of the impact of resistance phenotype acquisition on the virulence of C. glabrata isolates; in vitro evaluation by measuring cell invasion, cell adhesion and by determining epithelial cell cytotoxicity.; in vivo evaluation measured by a survival study on a CD-1 mouse model.
Clinical isolates sensitive to all antifungal agents; 10 clinical isolates sensitive to all	Other: in vitro evaluation of epithelial immune response during C. glabrata infection; study of the expression of genes coding for different proteins involved in the RTqPCR activation cascade; study of protein expression by the Western-Blot method; Other: study of the impact of resistance phenotype acquisition on the virulence of C. glabrata isolates; in vitro evaluation by measuring cell invasion, cell adhesion and by determining epithelial cell cytotoxicity.; in vivo evaluation measured by a survival study on a CD-1 mouse model.
Echinocandin-resistant clinical isolates; 10 echinocandin-resistant clinical isolates (Eucast, Caspofungin > 8µg/ml)	Other: in vitro evaluation of epithelial immune response during C. glabrata infection; study of the expression of genes coding for different proteins involved in the RTqPCR activation cascade; study of protein expression by the Western-Blot method; Other: study of the impact of resistance phenotype acquisition on the virulence of C. glabrata isolates; in vitro evaluation by measuring cell invasion, cell adhesion and by determining epithelial cell cytotoxicity.; in vivo evaluation measured by a survival study on a CD-1 mouse model.

What is the study measuring?

Primary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire Dijon

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2018
• Primary Completion (Anticipated): January 1, 2019
• Study Completion (Anticipated): June 1, 2019

Study Registration Dates

• First Submitted: August 28, 2018
• First Submitted That Met QC Criteria: August 28, 2018
• First Posted (Actual): August 29, 2018

Study Record Updates

• Last Update Posted (Actual): August 29, 2018
• Last Update Submitted That Met QC Criteria: August 28, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Bacterial Infections and Mycoses; Sepsis; Mycoses; Invasive Fungal Infections; Fungemia; Candidiasis; Candidiasis, Invasive; Candidemia
• Other Study ID Numbers: Basmaciyan AOI 2017

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No