Fungal infections have a major impact on human health. Fungi infect about 2 billion people and kill about 1.5 million people each year (greater than malaria or breast cancer). Life-threatening invasive fungal infections are hard to diagnose and treat, there are no effective antifungal vaccines, and intrinsic tolerance and acquired resistance to current antifungal drugs contribute to therapeutic failure. Clearly, clinicians require more effective antifungal therapies.
Candida species impose a high clinical and economic burden upon the European population. They frequently cause potentially fatal hospital-acquired bloodstream infections. These infections extend the time patients spend in intensive care units, increasing healthcare budgets by up to 1000 Euros per day per patient. Alarmingly, the mortality of severe sepsis caused by Candida is >50% (higher than for bacterial septicaemias) leading to an estimated >200,000 deaths annually worldwide. Candida species also cause oral thrush and vaginitis. Most women have suffered an episode of vulvovaginal candidiasis (VVC), with ~8% enduring recurrent infections.
The initiation and severity of a Candida infection depends on an intricate balance between the infecting fungal strain and the individual’s immune status and microbiota, all of which can display significant variability. Therefore, for the first time, FunHoMic integrates experts in fungal pathogenesis, immunology, microbial ecology and ‘omics to train 13 Early Stage Researchers (ESRs) who will define and exploit this Fungal-Host-Microbiota interplay to identify novel biomarkers (distinct 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) (Fig. 1A). FunHoMic ESRs will gain broad interdisciplinary skills plus a translational mindset through our integrated, inter-sectoral training program. This will allow Europe to remain at the forefront of translational research in the field of medical mycology.
To achieve this vision, the FunHoMic Network unites academic partners from France, Germany, The Netherlands, Switzerland, Spain and UK, a French Technology Research Institute and three SMEs from The Netherlands, Belgium and France (lien les partenaires sur le site internet).
The Fungal-Host-Microbiota interplay
Many fungal infections are caused by fungi that exist in healthy individuals without causing harm. Candida species are harmless colonizers of skin and mucosa where they interact with immune cells and other microbes. Yet they can transform into superficial or life-threatening pathogens under certain circumstances: e.g. antibiotic-induced microbial disturbance (dysbiosis), inborn or induced immune imbalance, or mucosal alterations. Indeed, variability in host genetics and immunity significantly affects the susceptibility of an individual to disseminated and/or mucosal candidiasis. Furthermore, an individual’s gut and mucosal microbiota composition influences their susceptibility to fungal infection. However, the mechanisms by which specific members of a healthy microbiota can provide protection against Candida outgrowth remain poorly understood. They may act directly on Candida cells, and/or modulate host immunity, offering potential as effective Live Biotherapeutic Products (LBPs). Variability in the fungal pathogen also influences the initiation and severity of fungal infections. Candida species vary considerably in their persistence as human commensals, their potency in superficial and disseminated infections, and their resistance to antifungal drugs. Furthermore, dramatic genetic and phenotypic diversity between clinical isolates underlies significant variability in their virulence and their ability to resist our innate immune defences. Most studies examine the impact of the fungus, the host or the microbiota independently.
Uniquely, FunHoMic will address how these variables impact the three-way interaction between the infecting isolate, the host immune status and the microbiota to provide an integrated perspective that has great potential value for precision medicine and patient management.