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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL096702-04
Application #
8461604
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Eu, Jerry Pc
Project Start
2010-05-01
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
4
Fiscal Year
2013
Total Cost
$385,225
Indirect Cost
$122,273
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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Werner, Jessica L; Steele, Chad (2014) Innate receptors and cellular defense against pulmonary infections. J Immunol 193:3842-50
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
Deak, Eszter; Nelson, Michael; Hernandez-Rodriguez, Yainitza et al. (2011) Aspergillus terreus accessory conidia are multinucleated, hyperpolarizing structures that display differential dectin staining and can induce heightened inflammatory responses in a pulmonary model of aspergillosis. Virulence 2:200-7
Nelson, Michael P; Christmann, Benjamin S; Werner, Jessica L et al. (2011) IL-33 and M2a alveolar macrophages promote lung defense against the atypical fungal pathogen Pneumocystis murina. J Immunol 186:2372-81
Werner, Jessica L; Gessner, Melissa A; Lilly, Lauren M et al. (2011) Neutrophils produce interleukin 17A (IL-17A) in a dectin-1- and IL-23-dependent manner during invasive fungal infection. Infect Immun 79:3966-77