An extracellular vesicle component as a candidate to control cryptococcosis

Summary fungal diseases are a major threat to immunocompromised patients. Cryptococcosis, caused by members of the cryptococcus genus, is responsible for nearly 200,000 deaths worldwide annually. Immunocompromised individuals are the primary population that develop cryptococcal meningoencephalitis, a 100% fatal condition if left untreated. C. Neoformans, the most common causative agent of cryptococcosis, has recently been classified as a critical threat by the world health organization. Despite their devastating impact on human health, fungal diseases have been consistently neglected, as demonstrated by the lack of available antifungal vaccines and our limited antifungal armamentarium. The rodrigues and nosanchuk laboratories have collaborated actively for over 15 years in the field of fungal infections and have extensively characterized fungal extracellular vesicles (EVS) in various models. EVS play crucial roles in fungal physiology and pathogenesis. Recently, we discovered that the tripeptide isoleucine-proline-isoleucine (IPI), a small molecule component of EVS, effectively controls cryptococcal infection in an invertebrate host. IPI acts as an inhibitor of dipeptidyl peptidase 4 (DPP4), which plays a role in fungal pathogenesis, as well as in host physiology, by regulating insulin and glucose. In this proposal, we aim to investigate the participation of IPI and DPP4 in fungal immunopathogenesis through three specific aims. Aim 1 will explore the protective mechanisms of IPI in animal models of cryptococcosis. Aim 2 focuses on understanding the roles of fungal and host DPP4 in disease progression, including their impact on glucose metabolism and the immune response. Aim 3 seeks to determine the relevance of IPI and DPP4 in other fungal models. Successful completion of this project will provide a comprehensive characterization of a novel candidate for combating cryptococcosis and perhaps other diseases. Furthermore, we anticipate gaining insights into the connection between DPP4 and fungal pathogenesis. This proposal aims to foster intercontinental collaboration and enhance the capabilities of fiocruz, the brazilian institution leading this collaborative effort.