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Deciphering the fungus-host-microbiota interplay to improve the management of fungal infections

Periodic Reporting for period 2 - FunHoMic (Deciphering the fungus-host-microbiota interplay to improve the management of fungal infections)

Periodo di rendicontazione: 2021-01-01 al 2023-06-30

The main goal of the FunHoMic project is to train 13 innovative, entrepreneurial and creative ESRs through an interdisciplinary and inter-sectoral research programme, which is based on the working hypothesis that susceptibility to fungal infections can be strongly influenced by the Fungal-Host-Microbiota interplay.
FunHoMic scientific objectives include
1) the establishment of new bioinformatic, organ-on-chip and gut simulation approaches to enhance the existing toolkit used to dissect the fungal-host-microbiota interplay during commensalism and pathogenicity;
2) the understanding of how C. albicans genetic variability impacts the fungal cell surface and metabolic adaptation to host niches and how this correlates with infectivity;
3) the exploration of how simultaneous variations of the host and microbiota influence C. albicans genetics and virulence to identify biomarkers of infection outcome; and
4) the investigation and exploitation of the mechanisms by which specific bacteria in the microbiota, including novel Live Biotherapeutic Product (LBP) candidates, impact C. albicans infectivity. These objectives are supported by an interdisciplinary, international, inter-sectoral training programme.

Some conclusions of the project:
- New technologies to the study of fungal infections such as organ-on-a-chip were introduced.
- Fermenters that can mimic the gastro intestinal tract were used and new tools were applied to analyse fungal microbiota.
- A subgroup of candida albicans isolates was found to only cause infections in the vagina.
- New avenues of research (from the project) include why some people harbour candida albicans while others do not, as well the impact of factors such as diet on infection rates.
In FunHoMic, 13 ESRs have been hired and have undertaken their respective research programs at the Partner institutions. Despite the major impact of the COVID-19 pandemics on the functioning of the laboratories, all ESRs have made significant progress in their research projects and the following achievements are to be pinpointed:
• A bioinformatics pipeline and fungal gene catalog, called FunOMIC, has been developed enabling both taxonomic and functional profiling of fungal genes. A corresponding user-friendly web server, Mycodm, has been developed.
• A fungal enrichment protocol has been developed.
• A cell line-derived gut-on-chip model has been optimized for studying fungal pathogenesis and applied to the study of a fungal peptide toxin, candidalysin, and the effect of short chain fatty acids.
• A patient-derived colon organoid gut-on-chip model has been developed and attempts to develop an oral mucosa-on-chip model were made.
• The Simulator of Human Intestinal Microbial Ecosystem (SHIME) system was shown to represent a valuable model to investigate fungal colonization in different gut compartments.
• Understanding of the genotypic and phenotypic specificities of the Candida africana cluster within the Candida albicans species was obtained.
• Exometabolome studies revealed extensive isolate-specific utilization of metabolites as well as cluster-specific differences, most notably the delineation of the C. africana cluster (impaired trehalose and choline utilization).
• Mutation pressure in cell wall-related genes was analysed, revealing genetic cluster-specific patterns. Genes harbouring potential cluster-specific gain-of-function mutations relevant to adhesion and biofilm formation have been pinpointed. Sensitivity to cell wall-perturbating agents also showed cluster-specificity.
• Antibiotic-induced alterations in the microbiota composition was shown to significantly aggravate systemic candidiasis progression.
• Gut colonization by C. albicans itself was shown to protect from systemic infection, with variation of this effect according to the colonizing C. albicans strain.
• A role of lactic acid, as well as acetic acid, in the outcome of the interaction of C. albicans with the host in the vaginal niche was observed.
• IL-17-dependent antimicrobial peptides have been identified at the origin for the IL-17-mediated restriction of C. albicans virulence in the oral niche.
• Two candidate host proteins, which may serve prognostic marker in RVVC have been identified.
• Analysis of C. albicans gastro-intestinal carriage in healthy individuals revealed factors that influence the level of carriage: diet-associated factors, host genetics.
• A culturomics approach performed using fecal sample from a healthy donor identified 11 bacterial strains with potential anti-Candida activities.
• Safety assessment of some candidate LBPs has been performed.
• The potentiation of the already commercialized LBP Lactobacillus rhamnosus Lcr35 by sodium thiosulfate was ascribed to the conversion of STS into sulfur.
• Elevated levels of short chain fatty acids (SCFAs) could explain the activity of LBPs towards C. albicans.

Importantly, work by the FunHoMic ESRs has led to 13 publications.
Understanding the interplay between fungi, the host and the body’s microbiota is critical to the development of more effective anti-fungal treatments. FunHoMic has helped us make significant progress towards this goal. Below are some achievements of the project.

Important methodological advances have been made such as:
- A bioinformatics pipeline and fungal gene catalog, called FunOMIC, has been developed enabling both taxonomic and functional profiling of fungal genes.
- A corresponding user-friendly web server, Mycodm, has been developed.
- A fungal enrichment protocol has been developed

New technologies have been used to study fungi:
- A patient-derived colon organoid gut-on-chip model has been developed; 3-D microfluidic cell cultures are integrated into a circuit chip, which then simulates the activities and mechanics of an organ system.
- Fermenters that can mimic the gastro intestinal tract were used.

Regarding the study of the host genetics and fungal diversity and genetics :
- The link between genetic diversity in Candida albicans and infection was examined. This allowed the discovery of a subgroup of candida albicans isolates that only causes infections in the vagina.
- The inability of this group of candida to thrive in other niches such as the gastro intestinal tract and the blood stream was demonstrated; a number of genetic markers were identified.
- Mutation pressure in cell wall-related genes was analysed, revealing genetic cluster-specific patterns.
- Two candidate host proteins, which may serve prognostic marker in RVVC have been identified

Live Biotherapeutic Products (LBPs)
- A culturomics approach performed using fecal sample from a healthy donor identified 11 bacterial strains with potential anti-Candida activities.
- Elevated levels of short chain fatty acids (SCFAs) could explain the activity of LBPs towards C. albicans

Dissemination of the activities of the FunHoMic consortium is achieved through its website www.funhomic.eu a twitter account @Funhomic_ITN and a LinkedIn account. ESRs have produced 13 publications within the timeframe of the project; several more are under review and will be published in the coming months.
ESRs have been also involved in poster and oral presentations as well as public outreach activities. A final FunHoMic conference was organized in Croatia with the participation of internationally renowned speakers and attendees.
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