Invasive pulmonary aspergillosis caused by the mold Aspergillus fumigatus has emerged as one of the most severe invasive fungal infections, not only in an expanding population of immunosuppressed patients, but also in individuals who are not considered classically immunocompromised. Innate immunity against A. fumigatus involves an initial wave of inflammatory reaction by alveolar macrophages followed by the seek-and- destroy mission of neutrophils. We have previously shown that the beta-glucan receptor Dectin-1 mediates alveolar macrophage (AM) inflammatory responses to A. fumigatus in vitro (Steele et al. PLoS Pathog 1:e42 Dec. 2005) and since the last review of this proposal (February 2009), we have now reported that mice deficient in Dectin-1 display an inherent susceptibility to A. fumigatus lung infection (Werner et al. J Immunol 182: 4938-4946, April 2009). A recent, intriguing finding was the observation that """"""""innate IL-17"""""""" was a central component of resistance to A. fumigatus: (1) Dectin-1 KO mice had a defect in lung IL-17 production shortly after A. fumigatus challenge and (2) WT mice administered IL-17 neutralizing antibodies became susceptible to A. fumigatus infection. We now show by intracellular cytokine staining that the predominant cellular sources of IL-17 in the lungs after A. fumigatus challenge are surprisingly not lymphoid in origin, but rather myeloid CD11b+ and CD11c+ cell populations, which produce IL-17 in a Dectin-1 dependent manner. In other data, we show that IL-6 and TGF-?, which are essential for the induction of Th17 cells, are not produced at lower levels in the lungs of Dectin-1 KO mice exposed to A. fumigatus, suggesting that other mechanisms/mediators are responsible for Dectin-1 dependent IL-17 production. In turn, new data indicate that production of the Th17/IL- 17 induction cytokine IL-21 and the Th17/IL-17 maintenance cytokine IL-23 are attenuated in Dectin-1 KO mice after A. fumigatus challenge, as are the chemokines CXCL12/SDF-1 and CCL2/MCP-1. These results suggest that Dectin-1 may control IL-17 levels in the lungs after A. fumigatus exposure via production of IL-17- associated induction cytokines or production of chemokines essential for the recruitment of IL-17-producing cells to the lungs. Finally, the Th17/IL-17 associated cytokine IL-22 was found to be highly dependent in Dectin-1 for its expression in the lungs. Therefore, we hypothesize that optimal IL-17-mediated defense against A. fumigatus is dependent on the beta glucan receptor Dectin-1. The following Specific Aims will test our hypothesis: (1) To identify the Dectin-1 dependent cellular source of IL-17 in the lungs after A. fumigatus exposure, (2) To identify the mechanism(s) responsible for Dectin-1 dependent, cell-specific production of IL-17 after A. fumigatus lung exposure and (3) To determine whether mediators associated with IL-17 induction (IL-21/IL-23), recruitment (SDF-1/MCP-1) and signaling (IL-22) pathways modulate lung host defense against A. fumigatus.
Our data indicate that the Dectin-1 beta-glucan receptor is essential for immunity against Aspergillus fumigatus, the etiological agent of invasive pulmonary aspergillosis, by controlling an innate IL-17 pathway that may be ultimately required for clearance of A. fumigatus from the lungs. Studies in this proposal will further characterize the cellular source of innate IL-17, the Dectin-1 dependent mechanisms for the generation of this cell population and whether IL-17 family members can modulate host defense against A. fumigatus.
|Reeder, Kristen M; Mackel, Joseph J; Godwin, Matthew S et al. (2018) The role of common ?-chain cytokines in lung IL-22 regulation after acute exposure to Aspergillus fumigatus. Infect Immun :|
|Garth, Jaleesa M; Reeder, Kristen M; Godwin, Matthew S et al. (2017) IL-33 Signaling Regulates Innate IL-17A and IL-22 Production via Suppression of Prostaglandin E2 during Lung Fungal Infection. J Immunol 199:2140-2148|
|Cruz, Fernanda F; Borg, Zachary D; Goodwin, Meagan et al. (2016) CD11b+ and Sca-1+ Cells Exert the Main Beneficial Effects of Systemically Administered Bone Marrow-Derived Mononuclear Cells in a Murine Model of Mixed Th2/Th17 Allergic Airway Inflammation. Stem Cells Transl Med 5:488-99|
|Cruz, Fernanda F; Borg, Zachary D; Goodwin, Meagan et al. (2015) Systemic Administration of Human Bone Marrow-Derived Mesenchymal Stromal Cell Extracellular Vesicles Ameliorates Aspergillus Hyphal Extract-Induced Allergic Airway Inflammation in Immunocompetent Mice. Stem Cells Transl Med 4:1302-16|
|Werner, Jessica L; Steele, Chad (2014) Innate receptors and cellular defense against pulmonary infections. J Immunol 193:3842-50|
|Lilly, Lauren M; Scopel, Michaella; Nelson, Michael P et al. (2014) Eosinophil deficiency compromises lung defense against Aspergillus fumigatus. Infect Immun 82:1315-25|
|Gessner, Melissa A; Werner, Jessica L; Lilly, Lauren M et al. (2012) Dectin-1-dependent interleukin-22 contributes to early innate lung defense against Aspergillus fumigatus. Infect Immun 80:410-7|
|Nelson, Michael P; Christmann, Benjamin S; Dunaway, Chad W et al. (2012) Experimental Pneumocystis lung infection promotes M2a alveolar macrophage-derived MMP12 production. Am J Physiol Lung Cell Mol Physiol 303:L469-75|
|Steele, Chad; Wormley Jr, Floyd L (2012) Immunology of fungal infections: lessons learned from animal models. Curr Opin Microbiol 15:413-9|
|Lilly, Lauren M; Gessner, Melissa A; Dunaway, Chad W et al. (2012) The ?-glucan receptor dectin-1 promotes lung immunopathology during fungal allergy via IL-22. J Immunol 189:3653-60|
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