Invasive fungal infections are associated with high mortality rates often exceeding 90%, adversely affecting immunocompromised patients, a rapidly growing patient population in the United States. The advent and use of immune modulating therapeutics aimed at treating devastating diseases such as autoimmune inflammatory syndromes (e.g. rheumatoid arthritis, Crohn's, ulcerative colitis) has provided patients with excellent control of their disease. Solid and bone marrow transplant patients have also benefited from a more potent arsenal of immune suppressive agents making more complicated donor-recipient organ matches a real possibility. Unfortunately, these biologic and chemotherapeutic agents are not specific and act to suppress immunity broadly, often leaving patients susceptible to severe invasive fungal infections including Candida, Aspergillus and dimorphic organisms, and represents a growing unmet need in our healthcare system. The process of fungal elimination begins with innate immune cell recognition of the carbohydrate-rich fungal cell wall followed by phagocytosis and the formation of phagolysosomes. Phagosomal maturation is a dynamic process that is central to the stimulation of lasting adaptive immunity, yet remains poorly understood. In this application, the candidate proposes a K08 Mentored Clinical Scientist Research Career Development Award grant that will address some of the critical subcellular molecular mechanisms required for fungal carbohydrate phagosomal maturation and their influence on T cell activation. To define the subcellular mechanisms in macrophages, a novel fungal-like particle system composed of carbohydrate-conjugated beads (FLP) was formed. ?-1,3-glucan FLP were used to analyze purified macrophage phagosomes. Data suggests that surface recognition of ? -1,3- glucan FLP by the lectin receptor, Dectin-1, controls acidification and phagolysosomal formation. The candidate hypothesizes that Dectin-1-specific signaling will dictate the composition of the recruited phagosomal protein repertoire. Specifically, the proposal aims will: 1) define the role Dectin-1 signaling in recruiting Rab7b to the fungal phagosome, 2) delineate the contribution of the NLRP3 inflammasome to phagosomal maturation, 3) determine the role of Dectin-1 signaling to class II MHC antigen presentation and CD4+ T cell stimulation. The candidate has completed a clinical fellowship in the combined Massachusetts General Hospital and Brigham and Women's Infectious Diseases Program. He has research experience in fungal immunity having studied anti-cryptococcal immunity, as part of his Ph.D. thesis work, which dovetails with his proposed training program. This career development grant outlines both didactic and practical bench- side research training focused on immune responses to fungal carbohydrates, improves our understanding of host-fungal interactions essential for the development of novel fungal vaccine strategies and provides the candidate with the necessary tools to develop into an independent biomedical investigator.
Invasive fungal infections are increasing due to a growing immunocompromised patient population. Phagocytosis of fungi is critical for elimination and stimulation of adaptive immunity. This project seeks to explain the molecular mechanisms involved in fungal phagosome maturation in order to develop novel fungal vaccine and immunotherapy strategies.
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