Immunity to pathogenic mucosal C. albicans infections mediated by oral megakaryocytes activated by IL-17 and candidalysin

Abstract

The fungus Candida albicans can cause mucosal infections including oropharyngeal candidiasis (OPC) in immunocompromised patients. In humans, an increased risk of fungal infections correlates with thrombocytopenia. However, our understanding of platelets and megakaryocytes in mucosal fungal infections is almost entirely unknown. When megakaryocyte- and platelet-depleted mice were infected with OPC, the tongue showed higher fungal burden, due to decreased neutrophil accumulation. Protection depended on a distinct population of oral-resident megakaryocytes. Interleukin-17, important in antifungal immunity, was required since mice lacking the IL-17 receptor had decreased circulating platelets and their oral megakaryocytes did not expand during OPC. The secretion of the peptide toxin candidalysin activated human megakaryocytes to release platelets with antifungal capacity. Infection with a candidalysin-deficient strain resulted in decreased expansion of tongue megakaryocytes during OPC. This is the first time that a distinct megakaryocyte population was identified in the oral mucosa that is critical for immunity against fungal infection.