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Activity Funded

Ecological role of Candida albicans in human microbiome: a case study for gastrointestinal dysbiosis

Papel ecológico de Candida albicans no microbioma humano: um caso de estudo para a disbiose gastrointestinal

Reference
2023.12236.PEX
Project Start Date
2025-01-01
Project End Date
2026-12-31
Principal Investigator
Scientific Area
Natural sciences
Funding Program
Concurso de Projetos Exploratórios em Todos os Domínios Científicos 2023

Abstract

Mycology is an area of urgent medical and research need, with more than 2.5 million deaths per year directly attributable to fungal infections, as a result of modern medicine practices and climate change. Due to the lack of effective antifungals and diagnostics, fungal infections are a serious global health threat . The yeast Candida albicans is a human commensal but also one of the most common fungal pathogens. C. albicans infections are particularly common in cancer patients, mainly due to gastrointestinal (GI) dysbiosis triggered either by broad-spectrum antibiotics or chemotherapeutic agents. Current epidemiological and experimental evidence supports C. albicans involvement in GI cancer, including an association of these pathogens with poor prognosis. The ability of C. albicans cells to inhabit a tumor raises two important questions: 1) are Candida species able to promote cancer as oncomicrobes? or 2) is the tumor ecosystem an attractive microenvironment that somehow fosters their proliferation and exacerbates cancer? GastroFungi aims to define the molecular mechanisms that underlie the involvement of C. albicans in GI carcinogenesis . This will clarify whether these pathogens play a causal or consequential role in the development of GI cancer. We propose to solve this at a mechanistic level by setting up a murine model of gastrointestinal cancer combined with C. albicans infections. We will use advanced imaging techniques and omics technologies to simultaneously profile and elucidate host-microbe mechanistic interactions. In parallel, we will investigate the dual role of the C. albicans plasma membrane G-protein-coupled receptor (CaGpr1) in regulating yeast-hyphae morphogenesis and beta-glucan masking during tumorigenesis, as we have hypothesized that both programs are required for successful tumor colonization. No in vitro model accurately reflects all aspects of the pathogenesis process, and so, the use of an in vivo model will offer our research team the unique opportunity to contribute with our expertise to the dissection of specialized genetic programs governing C. albicans infections. Although this spans biological fields (fungal and cancer biology), both type of disciplines are active within our research team. Still, our main focus is on deciphering the genetic programs of the microbe (fungal genetics and physiology), hence we propose that this project fits better within the Mycology field. Each task of our Research Plan contains well-defined milestones to ensure and check the action progress. We are confident that the strong multidisciplinary and interdisciplinary nature of the project minimizes the risks of failure. Yet, when they are present, alternative experiments are discussed. The generated knowledge of this project will serve as a solid basis for future studies comprising other medically relevant fungal species such as Candida (e.g. C. glabrata and C. auris ), Aspergillus or Cryptococcus . The project outputs will be monitored by the UMinho technology transfer office (TecMinho) to exploit its commercial potential; and will be disseminated in high impact, open-access scientific journals, conferences (attended by both fungal geneticists and clinicians) and non-academic audiences in order to target all potential stakeholders. This interdisciplinary network combining international collaborations with worldwide experts in fungal physiology and cancer biology , and an exchange of researchers between our laboratory and the laboratories abroad, will enhance the expertise and innovation in the field. One of the strategic objectives of our host institution, CBMA , is to promote fundamental studies on environmental - and human-pathogenic fungi with a view to provide solutions for the management of fungal infections. Thus, the goals of the current proposal are clearly aligned with CBMA's strategy. The programmed activities of scientific dissemination and public engagement are also integrated into the CBMA mission of fostering scientific literacy and knowledge translation to stakeholders, at national and international levels. The execution of GastroFungi will inherently provide new information on how C.albicans persistence is regulated during GI carcinogenesis , including how the tumour environment directly impacts the pathogenic behavior of these microbes, having the potential to reveal novel players of virulence pathways that can be exploited in search of new antifungal targets . Moreover, the effective management of Candida infections might be a sound preventive strategy or co-therapeutic option during oncologic tretaments.

Institutions

Main Institutions

  • Universidade do Minho (UMinho)

Other Institutions

  • Katholieke Universiteit Leuven (KULeuven)

Funding 50.000,00 €

Fundação para a Ciência e a Tecnologia (FCT) - Portugal

50.000,00 €