Dectin immunoadhesins and Pneumocystis pneumonia

… Blood oxygen saturation was 234 measured using a MouseOx pulse oximeter with a tail sensor
(Starr Life 235 Sciences, Oakmont, PA). … ketamine, the tail sensor was placed at the base of the
tail and measurements 237 were recorded using MouseOx software. … The opportunistic pathogen Pneumocystis jirovecii is a significant cause of disease in HIV-infected patients and others with immunosuppressive conditions.Pneumocystis can also cause complications in treatment following antiretroviral therapy or reversal of immunosuppressive therapy, as the newly reconstituted immune system can develop a pathologic inflammatory response to remaining antigens or a previously undetected infection. To target β- (1, 3)-glucan, a structural component of the Pneumocystis cell wall with immune-stimulating properties, we have developed immunoadhesins consisting of the carbohydrate-binding domain of Dectin-1 fused to the Fc regions of the 4 subtypes of murine IgG. These immunoadhesins bind β-glucan with high affinity, and precoating the surface of zymosan with Dectin-1:Fc can reduce cytokine production by macrophages in an in vitro stimulation assay. All Dectin-1:Fc variants showed specificity of binding to the asci of P. murina, but effector activity of the fusion molecules varied depending on Fc subtype. Dectin-1:mIgG2a Fc was able to reduce the viability of P. murina in culture through a complement-dependent mechanism, whereas previous studies have shown the mIgG1 Fc fusion to increase macrophage-dependent killing. In an in vivo challenge model, systemic expression of Dectin-1:mIgG1 Fc significantly reduced ascus burden in the lung. When administered post-infection in a model of immune reconstitution inflammatory syndrome (IRIS), both Dectin-1:mIgG1 and mIgG2a Fc reduced hypoxemia despite minimal effects on fungal burden in the lung. Taken together, these data indicate that molecules targeting β-glucan may provide a mechanism for treatment of fungal infection and for modulation of the inflammatory response to Pneumocystis and other pathogens.