Advisory Committee Chair
Advisory Committee Members
Date of Award
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Immune suppression increases the incidence of invasive fungal infections, particularly those caused by the opportunistic mold Aspergillus fumigatus. We show that non-immunosuppressed mice lacking the beta-glucan receptor Dectin-1 (Dectin-1-/-) are more susceptible to intratracheal challenge with A. fumigatus than control mice, exhibiting >80% mortality within 5 days; ultimately attributed to a compromise in respiratory mechanics. In response to A. fumigatus challenge, Dectin-1-/- mice demonstrated impaired inflammatory response as seen through defective cytokine and chemokine production, which resulted in insufficient lung neutrophil recruitment and uncontrolled A. fumigatus lung growth. Alveolar macrophages from Dectin-1-/- mice failed to produce proinflammatory mediators in response to A. fumigatus, while neutrophils from Dectin-1-/- mice had impaired reactive oxygen species production and impaired killing of A. fumigatus. We further show that interleukin-17 (IL-17) production in the lung after A. fumigatus challenge was Dectin-1 dependent and that neutralization of IL-17 significantly impaired A. fumigatus clearance. IL-17 production by cultured lung digest cells from A. fumigatus infected mice was also Dectin-1 dependent. In cultured lung digest cells, neutralization of IL-23 reduced IL-17 production, with IL-6, IL-1ß or IL-18 having no effect. The addition of recombinant IL-23 markedly increased IL-17 production by both wild type and Dectin-1-/- lung digest cells in a Dectin-1 dependent fashion. Intracellular cytokine staining of cells from infected lungs revealed that while myeloid cells produce a large amount of IL-17, only neutrophils produce IL-17 in a Dectin-1 dependent manner. Neutrophils cultured alone or with IL-23, but without the addition of myeloid cells were unable to produce IL-17. Finally, thioglycollate-elicited peritoneal neutrophils stimulated with A. fumigatus were positive for intracellular IL-17; and IL-17 production was both Dectin-1 and IL-23 dependent. In conclusion, Dectin-1 is required for innate host defense against A. fumigatus; which is mediated by the production of IL-17 by neutrophils in a IL-23 dependent manner.
Werner, Jessica L., "The Requisite Role of Dectin-1 and IL-17 in Innate Host Defense Against Aspergillus fumigatus" (2011). All ETDs from UAB. 3303.