Innate Immune Response to Aspergillus fumigatus Cell Wall Carbohydrates

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Project Summary/Abstract Invasive fungal infections are associated with exceptionally high mortality rates often exceeding 80%, and are increasing in incidence due to a rapidly growing population of immunocompromised patients. Aspergillus fumigatus is one of the leading causes of invasive fungal infections and causes a spectrum of diseases ranging from skin and soft tissue to disseminated infections. Amongst patients that received hematopoietic or solid- organ transplants, approximately 10% will develop invasive aspergillosis. The persistently high mortality rates despite antifungal therapy highlights the deficiencies in our current antifungal armamentarium and the critical role that the immune system plays in the clearance of infections. Effective fungal immunity is initiated by innate immune recognition of the complex, carbohydrate fungal cell wall followed by cytokine production, ROS generation, phagocytosis and killing of pathogens. The profile of fungal carbohydrate antigens displayed on the fungal cell wall dictates the pattern recognition receptors engaged and influences whether a protective or non- protective response is generated. In this application, the candidate proposes a K08 Mentored Clinical Scientist Research Career Development Award grant that will characterize molecular mechanisms of macrophages and neutrophil response to the A. fumigatus carbohydrates, galactomannan (GALM) and galactosaminogalactan (GAG). To define the subcellular pathways involved in the response to these carbohydrates, novel fungal like particles (FLP) composed of single purified carbohydrates stably coating polystyrene beads will be utilized. Preliminary data suggests that Dectin-2 is a receptor for GALM. Specific Aim 1 will define the role of Dectin-2 in macrophages and neutrophil recognition and response to both soluble and cell wall associated GALM, specifically probing the role of Dectin-2 and the downstream effector Syk in cytokine production, phagocytosis, and phagosomal maturation. Specific Aim 2 seeks to define the molecular pathways that mediate macrophage and neutrophil responses to soluble and cell wall-associated GAG. This aim will define signaling pathways and receptors critical for GAG mediated immunosuppression and define the role of GAG in cytokine production, ROS generation, and phagocytosis. The candidate is a physician-scientist and has completed a clinical fellowship in the combined Massachusetts General Hospital and Brigham and Women's Infectious Diseases Program. She has research experience in fungal molecular biology having devoted her graduate training to defining signaling pathways involved in virulence and the generation of diversity in the human pathogens, Candida and Cryptococcus. Her overall career goal is to be an independent investigator capable of probing the host-pathogen interface. Therefore this career development grant outlines a didactic, mentoring, and scientific research plan that will provide the necessary training in host immunology necessary to study the dynamic interplay between host and pathogen and become a productive independent physician-scientist.