Title: Investigating the influence of platelet-derived eicosanoids on NET formation during fungal infection
Funder: The Academy of Medical Sciences

Abstract: Each year, severe fungal diseases affect >150 million people worldwide. C.albicans and A.fumigatus cause the majority of bloodstream infections and mortality (1.6 million). Emerging antifungal drug resistance severely limits treatment options, therefore, a better understanding of immunity underlying fungal infections is imperative to discover new therapeutics. Platelet-neutrophil crosstalk is important in fungal immunity, since thrombocytopenia and neutropenia increase invasive fungal infection risk. Neutrophils release neutrophil extracellular traps (NETs), that ensnare C.albicans and A.fumigatus and prevent them from spreading in the blood. NET formation to trap fungi is modulated by macrophage-derived prostaglandin(PG)E2. How platelets modulate immunity and, in particular, NET response to fungi is unclear. My preliminary experiments suggest that gliotoxin (metabolite of several pathogens including A.fumigatus), inhibits platelet aggregation and release of TxA2; while zymosan (fungal cell wall surrogate) supports platelet aggregation. Gliotoxin prevents platelet-neutrophil interaction and NET formation, while zymosan has the opposite effect. I hypothesise that platelet-derived eicosanoids, including PGE2 and TxA2, modulate NET formation in response to fungi. To test this hypothesis, I will: 1.Dissect the effects of fungal pathogens (C.albicans, A.fumigatus), their toxins (candidalysin and gliotoxin), and cell wall components (zymosan), on platelet activation and eicosanoid profiles. 2.Determine whether platelet-released eicosanoids modulate NET-formation in response to fungi and their components. 3.Elucidate if fungi induce platelets to release eicosanoid-rich microvesicles affecting NET formation. This proposal will lead to understanding the involvement of platelet-derived eicosanoids in fungal immunity. Modulating platelet activation and eicosanoid release could offer a therapeutic option for fungal diseases.

Lay abstract: Fungal infections affect over a billion of people in the world, they can be caused by airborne pathogens like A.fumigatus or by species, like C.albicans, normally living in our body, for example in the gastro-intestinal tract. When patients have an impaired immune system because of treatments for health problems including cancer, organ transplantation and steroid therapies, fungi can enter the blood and cause severe infections. It is estimated that these infections kill more than 1.5 million people each year and is made worse because many fungal species have become resistant to treatments. Therefore, new medicines that prevent fungi from spreading in the blood and causing severe disease are urgently needed. Platelets are the smallest cells in the blood known for their role in blood clotting. More recently they have also been shown to be important in fighting bacterial and viral infections by helping specialised white blood cells called neutrophils to release neutrophil extracellular traps (NETs), ‘microbe traps’ that capture and destroy pathogens. However, the contribution of platelets to this immune response to fungi is not clear. I will investigate how fungi affect the function of platelets and their communication with neutrophils to produce NETs that trap and remove fungi. Importantly, the effects on NET formation by common drugs, such as aspirin, which block platelet function will be tested. Understanding how platelets contribute to fungal infections in the blood, will enable more effective antifungal treatments to be developed which will improve outcomes for patients, particularly those who have weakened immune systems.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION