title: Dectin immunoadhesins and pneumocystis pneumonia.
abstract: 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 pathological 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 (mIgG). 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 Pneumocystis 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 postinfection in a model of immune reconstitution inflammatory syndrome (IRIS), both Dectin-1:mIgG1 and Dectin-1: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.
authors.affiliation: Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Ricks
authors.forename: Kong
authors.initials: K
authors.lastname: Chen
authors.forename: Mingquan
authors.initials: M
authors.lastname: Zheng
authors.forename: Chad
authors.initials: C
authors.lastname: Steele
authors.forename: Jay K
authors.initials: JK
authors.lastname: Kolls
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D002473:Cell Wall / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D054019:Immune Reconstitution Inflammatory Syndrome / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D007249:Inflammation / Q000276:immunology; D037181:Lectins, C-Type / Q000276:immunology*; D008168:Lung / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D011020:Pneumonia, Pneumocystis / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D015054:Zymosan / Q000276:immunology; D047071:beta-Glucans / Q000276:immunology; D000099181:Dectin-1
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; D007074:Immunoglobulin G; D037181:Lectins, C-Type; D015054:Zymosan; D047071:beta-Glucans; D000099181:Dectin-1