Enhanced Defense against Pneumocystis carinii Mediated by a Novel Dectin-1 Receptor Fc Fusion Protein

• Published in: Journal of Immunology Vol. 178; no. 6; pp. 3702 - 3712
• Main Authors: Rapaka, Rekha R, Goetzman, Eric S, Zheng, Mingquan, Vockley, Jerry, McKinley, Laura, Kolls, Jay K, Steele, Chad
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15-03-2007
• Subjects: Adenoviridae; AIDS-Related Opportunistic Infections - immunology; AIDS-Related Opportunistic Infections - prevention & control; Animals; Antibody-Dependent Cell Cytotoxicity - drug effects; Antibody-Dependent Cell Cytotoxicity - genetics; beta-Glucans - immunology; Disease Models, Animal; Human immunodeficiency virus; Humans; Immunocompromised Host - immunology; Immunoglobulin Constant Regions - genetics; Immunoglobulin Constant Regions - pharmacology; Lectins, C-Type; Lung - immunology; Lung - microbiology; Macrophages, Alveolar - immunology; Male; Membrane Proteins - genetics; Membrane Proteins - pharmacology; Mice; Mice, SCID; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - pharmacology; Pneumocystis carinii; Pneumocystis carinii - immunology; Pneumonia, Pneumocystis - immunology; Pneumonia, Pneumocystis - therapy; Receptors, IgG - agonists; Receptors, IgG - immunology; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - pharmacology
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.178.6.3702

Pneumocystis carinii (PC) pneumonia is a leading opportunistic infection found among HIV-infected individuals worldwide. Although CD4(+) T cell deficiency clearly correlates with susceptibility to PC pneumonia, murine models of disease indicate that PC-directed Abs may prevent infection and/or inhibit growth of existing PC within the lungs. Recognition of PC by alveolar macrophages involves the beta-glucan receptor Dectin-1 and macrophage effector function against PC is enhanced by Abs derived from PC-vaccinated hosts. We developed a fusion protein consisting of the extracellular domain of Dectin-1 linked to the Fc portion of murine IgG1, which we hypothesized would enhance host recognition and opsonic phagocytosis of PC. The recombinant protein, Dectin-Fc, is dimeric and the Ag recognition site identifies beta-1,3 glucan linkages specifically and with high affinity (K(D) = 2.03 x 10(-7) M). Dectin-Fc enhances RAW264.7 macrophage recognition of the beta-glucan containing particulate zymosan in an FcgammaRII- and FcgammaRIII-dependent manner and preopsonization of PC organisms with Dectin-Fc increased alveolar and peritoneal macrophage-dependent killing of PC. SCID mice treated with a replication incompetent adenoviral vector expressing Dectin-Fc had attenuated growth of PC within the lungs, overall decreased PC lung burden, and diminished correlates of PC-related lung damage relative to SCID mice receiving a control vector. These findings demonstrate that targeting PC beta-glucan with Dectin-Fc enhances host recognition and clearance of PC in the absence of B and T cells, and suggest that FcgammaR-based targeting of PC, via cell wall carbohydrate recognition, may promote resistance against PC pneumonia in the immunodeficient host.