A soluble Dectin-1 Fc fusion protein enhances innate immunity against invasive pulmonary aspergillosis

The Dectin-1 beta-glucan receptor is essential for alveolar macrophage (AM)-mediated defense against Aspergillus fumigatus. Increased incidence of invasive pulmonary aspergillosis (IPA) over the last several decades has necessitated the development of novel vaccines and immunotherapies to augment host defense against A. fumigatus in susceptible individuals. In our studies, the extracellular carbohydrate binding domain of Dectin-1 was fused with murine IgG1 Fc (sDect-Fc) by PCR and cloned into a mammalian expression vector. sDect-Fc was also cloned into a non-replicating adenovirus for in vivo expression. The viability index (VI) in AM cultures containing sDect-Fc was 80% lower than untreated AM cultures, indicating sDect-Fc significantly augments AM-mediated killing of swollen conidia. sDect-Fc also minimized the AM inflammatory response to A. fumigatus. IV administration of AdsDect-Fc, but not AdLuc, to naive mice resulted in sDect-Fc protein in the lungs. In preliminary studies, mice receiving AdLuc had 66% mortality within 16 days after A. fumigatus challenge whereas mice that received AdsDect-Fc had no mortality within a 21 day period. These results support the use of sDect-Fc as an immunotherapeutic strategy to augment host defense against IPA. Grant HL080317 from the NIH and grant CI-21330-N from the ALA.