Dissecting and harnessing lung defense mechanisms against inhaled fungal spores.

Advances in medical technology, exemplified by transplantation, myeloablation, and immunosuppression, have revolutionized the treatment of organ failure, cancer, and autoimmunity. In turn, the number of people that live in immune suppressed states has increased dramatically in the past 2-3 decades. In this growing cohort of patients, invasive fungal infections are on the rise and represent a clinical problem with unsatisfactory treatment options and outcomes.

Our laboratory research focuses on the host-pathogen relationship between medically relevant fungi and the vertebrate immune system. Invasive aspergillosis is the most common invasive mold infection worldwide and represents a major cause of infectious morbidity and mortality in patients that receive treatment for leukemia or undergo bone marrow transplantation. Our goal is to develop a detailed mechanistic understanding of molecular and cellular host defenses against Aspergillus fumigatus, the most common etiologic agent of invasive aspergillosis in order to develop novel strategies to augment or supplement current antifungal drugs. To this end, we use in vitro cell culture systems and murine infection models and rely on cell biological, biochemical, immunological, and imaging techniques to probe the host-pathogen interface.

The key event that determines the outcome of infection is restriction of spore germination into filamentous hyphae. The signaling receptor dectin-1 underlies, in part, host recognition of spores and binds to a fungal polysaccharide, beta-glucan, that is obligately exposed on the cell surface during the germination process. This response is enhanced by treating fungal cells with antifungal agents that belong to the echinocandin drug class, a process that results in increased beta-glucan exposure on A. fumigatus filaments. We are examining this signaling cascade in the development of innate and adaptive immune responses to A. fumigatus.

Another focus of the laboratory is to examine the role of specific resident and recruited cells in pulmonary host defense. To this end, we have established inducible cell ablation techniques in the laboratory. These include in vivo administration of a bacterial toxin to induce apoptosis in genetically defined murine cell populations, for example monocytes, and the use of toxin-containing liposomes that permit lung and airway macrophage depletion. These techniques have enabled us to examine the contribution of alveolar macrophages, monocytes, and neutrophils to specific host defense functions.