Periodic Reporting for period 1 - FunHoMic (Deciphering the fungus-host-microbiota interplay to improve the management of fungal infections) Reporting period: 2019-01-01 to 2020-12-31 Summary of the context and overall objectives of the project 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. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far In the reporting period, the 13 ESRs have been hired and have undertaken their respective research programs at the Partner institutions, but also through secondments. 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 comprehensive fungal gene catalog database for future metaomics studies is being established• A method to assess fungal load in fecal and lower biomass samples, such as rectal swabs, has been developed• The impact of short-chain fatty acids and C. albicans virulence factors on epithelial integrity has been investigated using a gut-on-chip approach• An oral-on chip model is being developed• A simulator of the physiological and microbial GI tract system was shown to be valuable to investigate colonization of the GI tract by pathogenic yeast species• Extensive phenotyping of the so-called C. africana strains, a cluster in the C. albicans population, has revealed unique stress sensitivity and antifungal tolerance• Nonsense mutations unique to C. africana have been identified that may explain the niche specificity of these isolates, which is currently investigated using a combination of molecular genetics and ex vivo/in vivo infection models• Nonsense mutations have been identified in genes important for cell wall biogenesis and their link to phenotypic variation is investigated• Methods for metabolomic, lipidomic, and proteomic have been put in place that will allow extensive profiling of genome-sequenced isolates• The involvement of several genes related to the exposure Microbial-Associated Molecular Patterns in sensitivity to cell wall stressors has been investigated• Variability in the exposure of molecular moieties on C. albicans cell wall was shown to affect the host immune response differently• The impact of intraspecies variability and of the microbiota on gastro-intestinal colonization has been investigated• The impact of specific metabolites found in the vaginal environment on C. albicans impact on the host response – cytokine, ROS production, phagocytosis, trained immunity – was characterized• Adaptive changes experienced by C. albicans in the context of commesalism or pathogenesis in the oral niche has been investigated• A metagenomic approach to identify C. albicans-antagonistic microbes of healthy individuals having received an antibiotic treatment has been developed.• Besides, a culturomic approach has been developed to also identify C. albicans-antagonistic microbes present in fecal samples• The mechanisms by which Lactobacillus rhamnosus impacts C. albicans damage to vaginal epithelial cells are under investigation• The relationship between the LBP L. rhamnosus Lcr35 and sodium thiosulphate is being deciphered• The impact of short chain fatty acids on C. albicans has been investigated. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) Results obtained by all ESRs during the first reporting are in line with the planned schedule of the research program, although the COVID pandemic has impacted both the research projects and the secondments. Important methodological advances have been made that will be leveraged during the coming months. At this stage, it is still challenging to define the socio-economic impact that the FunHoMic data will have. Yet, it is expected that FunHoMic’s investigation of the Fungal-Host-Microbiota interplay will identify novel biomarkers (fungal or host genetic polymorphisms, microbiota profiles, metabolites or immune markers) for the stratification of a patient’s risk of serious fungal infection. This will pave the way for precision medicine in patient management through preventive or therapeutic interventions using antifungals, immune modulators or Live Biotherapeutic Products (LBPs). 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. Several publications, in addition to the review mentioned above, have already been authored by the ESRs who have been also involved in poster and oral presentations as well as public outreach activities.