Program Director/Principal Investigator (Last, First, Middle): 1R01AI068917 - 01A2 PI Name: STEELE, CHAD ABSTRACT Immunosuppression associated with hematopoietic stem cell or solid organ transplantation results in a significant predisposition to invasive fungal infections, particularly those caused by Aspergillus fumigatus. We have previously reported that interruption of recognition by the beta-glucan receptor Dectin-1 attenuated alveolar macrophage inflammatory responses to A. fumigatus in vitro. Here, we show that immunocompetent mice lacking Dectin-1 (Dectin-1-/-) are inherently sensitive to intratracheal challenge with A. fumigatus, exhibiting >80% mortality within 5 days, ultimately as a result of compromised lung function. Twenty-four hours after challenge, Dectin-1-/- mice had impaired proinflammatory cytokine and chemokine production which resulted in blunted lung neutrophil recruitment and subsequent uncontrolled A. fumigatus lung growth. Histological assessment provided further evidence for both defective neutrophil recruitment and aberrant neutrophil recognition of A. fumigatus in Dectin-1-/- mice. In vitro studies indicated that A. fumigatus failed to induce proinflammatory responses from Dectin-1-/- alveolar macrophages whereas Dectin-1-/- neutrophils were unable to kill A. fumigatus. Collectively, these results support a fundamental role for Dectin-1 in the generation of macrophage-derived neutrophil recruitment signals as well as in neutrophil-mediated containment of pulmonary A. fumigatus. Moreover, we further show in preliminary studies that IL-1. and IL-1?are essential mediators of innate immunity against A. fumigatus in vivo. Taken collectively, our data support the concept that Dectin-1 is one of the earliest recognition pathways involved in the host response to A. fumigatus. Therefore, our central hypothesis is that the Dectin-1 beta glucan receptor is required for immunity against A. fumigatus and successful host defense against invasive pulmonary aspergillosis. We plan to test our hypothesis with the following Specific Aims: (1) To test the hypothesis that Dectin-1 is required for innate and adaptive immune function against A. fumigatus and (2) To test the hypothesis that IL-1 is essential for immunity to A. fumigatus. The results of these studies will provide invaluable insight into first-line defense mechanisms against A. fumigatus and will hopefully lead us to develop novel immunotherapeutic strategies to augment host defense against A. fumigatus in susceptible individuals.
Our data indicates that the Dectin-1 beta-glucan receptor is essential for defense against Aspergillus fumigatus, the etiological agent of invasive pulmonary aspergillosis (IPA). In this proposal, we will uncover innate anti-fungal mechanisms mediated by Dectin-1 expressing immune cells and determine the role of Dectin-1 in adaptive immune responses. We will also characterize the role of the proinflammatory cytokine IL-1 in protection against IPA and examine the efficiacy of a immunotherapeutic fusion protein that we have development for the treatment of IPA.
