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An iron armor against fungal pathogens

Research group photo and a glimpse of fungus from a microscope

Researchers are working to reduce the risk of life-threatening infections due to fungal diseases

Patients with a weakened immune system are at constant risk of life-threatening infections by opportunistic organisms, including airborne saprophytic fungi (fungi feeding on dead organic matter). Nowadays, fungal diseases are occurring more frequently because of the increasing number of patients with acquired immune defects, including patients on ‹targeted› therapies for malignant and autoimmune diseases and those recovering from sepsis syndromes (e.g., influenza, COVID-19).

Fungal diseases are associated with high mortality rates, especially among patients with deregulated iron metabolism, due to the lack of efficient treatments.

The group of George Chamilos at FORTH-IMBB, a EU-LIFE partner institute, is studying how the immune system fights off these infectious fungal diseases.

George Chamilos was raised in a village of South Crete, Greece, where helping people in need has been a core value of this small society, so he decided to become a doctor. Over the years, his daily interaction with patients who suffered from terminal stage diseases made him realize that medical doctors are often powerless to fight against them and efficiently help those people. After finishing his residency in Greece, he visited the US to perform research and a clinical fellowship in infectious diseases at a major cancer Institute, where he discovered that traditional antimicrobial therapies offered very little to immunocompromised patients who suffered from fungal diseases. Over half of these patients died from disseminated fungal infection while in complete remission from cancer, despite the fact that they had received appropriate therapy with potent antifungal agents. 

This experience made him realize the major gap in knowledge on the pathogenesis of infections in the immunocompromised host and the need to invest in fundamental research for development of host-directed therapies aiming to restore immune deregulation in these patients. He was determined at that point that he should pursue this research path.

However, research was challenging during the first years of his return from the US to Greece. At the beginning of his career as a Principal Investigator, George had limited resources and time for research. A successful application for a Marie Curie Reintegration Grant was the driving force that allowed him to continue in research and develop his career as a scientist.  During that time, he used a tiny fruit fly called Drosophila melanogaster as a research model since it is easy to grow in the lab, it has a short life cycle and an evolutionary conserved immune system.

Macrophages are the ‹frontline soldiers› of our immune system that patrol the human body and swiftly eat up foreign particles, microbial pathogens (bacteria and fungi) and dying cells (a process called phagocytosis) to maintain our body’s health. Amazingly, they have remarkable similarities with the macrophages of fruit flies.

Chamilos› group discovered that the presence of melanin (a pigment that normally protects us from sun radiation and is responsible for the dark color of our skin) on the cell surface of fungi protects them from elimination by macrophages by inhibiting the process of phagocytosis and affecting iron metabolism. These findings were of great interest and led to securing a prestigious grant of 1.5 million euros from the European Research Council.

The group will now exploit their fungal infection model in Drosophila to perform targeted genetic screens to identify the master regulators of iron metabolism in macrophages and how they orchestrate protective immunity against fungal pathogens. This way, the group will uncover evolutionarily conserved mechanisms of protective immunity mediated by iron inside macrophages. At the next stage, they will extend their research to mammalian macrophages in mice, and finally human patients, to validate their results.

Chamilos hopes that his current work will result in the development of an alternative class of drugs that can fight fungal infections by optimizing the host immune response to resolve the immunopathology of the disease rather than targeting the pathogen with the use of traditional antimicrobial therapies.

Chamilos never forgets the patients he failed to cure. Their memory has been a driving force in his career, to keep on learning and trying harder. He admits that working on a challenging quest awakens one’s passion for research and fosters creative thinking to resolve complex scientific problems. He is grateful for the grants that helped him develop his research, the outstanding members of his group that carried out all the research, his long-term international collaborators, and is a strong advocate that the European Union should increase investment in discovery-driven research.

Story by Eva Zacharioudaki (IMBB-FORTH) / Photo: Christos Tsoumplekas