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Molecular Mechanisms of Fungal Pathogen Host Interactions

Final Report Summary - IMRESFUN (Molecular Mechanisms of Fungal Pathogen Host Interactions)

The advancement of medicine in the past century has been one of the most successful stories of mankind, resulting in a significant increase in life-expectance by providing better access to high-quality medical technologies and treatments. Nevertheless, infectious diseases remain as the most prevalent health threat and cause of mortality. The major causes of human mortality are due to existing and emerging fungal, parasitic, bacterial and viral pathogens. Moreover, pronounced and ever-emerging anti-infective drug resistance poses a major obstacle to successful therapy. Indeed, according to the World Health Organization (WHO), despite the success of anti-infective drugs and vaccines, microbial pathogens stand out as the major cause of death, accounting for some 35% of mortalities worldwide. The spread of anti-infective resistance has attracted the increased awareness of funding agencies, political stakeholders and scientists throughout the world to devote special attention to the detection, prevention and eradication of pathogens prone to develop multidrug-resistance phenotypes that impair clinical therapies.
Notably, fungal infections are a leading cause of morbidity and mortality for hospitalized patients, particularly in cases of immune deficiencies, predominantly due to inefficient diagnosis and treatment regimens. Hence, fungal infections represent a major socio-economic and clinical problem for worldwide communities, and remain a high priority challenge for global healthcare provision, demanding permanent attention in translational biomedical research. Thus, novel anti-infectives, as well as fast and reliable clinical diagnosis and identification of new disease biomarkers are of key importance in our combat against fungal infections. Especially fungal pathogens colonizing hosts as commensal organisms, the so-called opportunistic pathogens, constitute an ever-growing healthcare threat.
Many fungal pathogens are notoriously opportunists, being highly detrimental to patients with haematologic–oncologic diseases, with neutropenia or after organ transplants. Due to their eukaryotic nature, fungi are especially difficult to treat, with mortalities of invasive bloodstream infections ranging from 40-90%. Importantly, Candida spp represent the third to fourth-most common cause of nosocomial infections. Fungal infections can be considered hidden killers, since they claim more than 1,5 million lifes every year, and are thus more deadly than most bacterial infections including gram-negative septicaemias. Thus, ever-increasing numbers of fungal diseases cause annual healthcare costs exceeding double-digit billions in USA and Europe. Personalized medicine in cancer and infectious diseases, as well as host-pathogen interactions are therefore currently among the most timely and competitive research areas addressing unmet needs in translational research. Nevertheless, the mechanisms underlying infectious processes remain poorly understood, particularly those caused by fungal pathogens. While life expectancy has increased significantly, even for individuals with acute, inherent or chronic malfunctions of the immune system, individuals and the elderly are particularly susceptible to nosocomial infections caused by microbial pathogens. Remarkably, most recent path-breaking studies provide compelling proof that microbiome dysbiosis of the intestine caused by fungal colonizers of the human gut such as Candida spp are tightly linked to chronic inflammatory diseases such as Intestinal Bowel Disease (IBD) or other autoimmune disorders that result from malregulated colonization by commensal fungi.
ImResFun contributed to the main pillars of European-funded health research such as (i) translating research results into products for improving human health and biotechnology, and (ii) generating generic tools and medical technologies to improve human healthcare. ImResFun trains competitive scientists for future challenges in the European human health sector, especially when considering the emerging threats for public health and the ageing population susceptible to nosocomial microbial infections, all of which requires the cooperation of emerging supra-disciplinary fields, including infection systems biology. ImResFun united a total of 12 partners from academic, applied research institutions and SMEs to provide supra-disciplinary and inter-sectorial research training in microbial infectious diseases covering fields from chemical biology, drug development, clinical microbiology, diagnostics of fungal pathogens as well as bioinformatics at the highest technical and scientific levels. The major aim of ImResFun was to provide state-of-the-art training in infectious disease research and fungal immunology by targeting the most prevalent human fungal pathogens, the opportunistic Candida species that colonize humans. The key objectives of ImResFun were:
• to understand how immune cells and infected organs respond to invasion by Candida spp,
• to decipher host-defense mechanisms mediating pathogen surveillance and elimination
• to identify genetic regulatory networks driving the dynamics of host-pathogen interplay
• to improve clinical diagnosis and identify novel biomarkers of fungal infections
ImResFun exploited cutting-edge technologies to unravel basic mechanisms of fungal pathogenesis and host immunity, and, importantly, ImResFun translated basic biomedical research into clinical practice by identifying potential targets for antifungal drug discovery. The research and training conducted in ImResFun was distributed among several work packages (WP), and covered studies on molecular mechanisms of host-pathogen interactions using dual-system infection biology (WP1), clinical patient setting and age-related infections (WP2), chemical biology and antifungal development (WP3), and bioinformatics of genome-wide data analysis, including the development of novel algorithms allowing for the analysis of genomic and genetic datasets (WP4).
All ERs/ESRs participated in compulsory and tailor-made practical (WP5) and complementary skills courses (WP6) to support their research projects. Meaningful exposure to the private sector was ensured by secondments of all ERs/ESRs to industrial partners. Furthermore, ImResFun established personalized career development plans for each ESR/ER, emphasizing their training to become entrepreneurial scientists capable of translating frontier research into clinical practice, biotechnology and drug discovery.
Taken together, ImResFun constituted a best-practice example for interdisciplinary training in a highly timely infection disease research area, all in all, aiming for a better understanding of the dynamics and complexity underlying the host immune response to the most prevalent human fungal pathogens.
We are confident to state that ImResFun will have an impact on our understanding of the immunology of invasive fungal diseases including clinical practice and therapy. Fungal infections are of enormous socioeconomic impact due to their high economic burden for modern healthcare systems, underpinning the global societal implications of infectious disease research.

Further details and information about the ImResFun ITN (Contract MC-ITN-606786) can be obtained from the website (www.imresfun.org). You may also contact the Coordinator’s Office by e-mail using the contact info@imresfun.org