Enhanced defense against Pneumocystis carinii mediated by a novel dectin-1 receptor Fc fusion protein.
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.
Rapaka
Rekha R
RR
Department of Pediatrics, Division of Pulmonary Medicine, Allergy, and Immunology, Children's Hospital of Pittsburgh, Pittsburgh, PA 15213, USA.
Goetzman
Eric S
ES
Zheng
Mingquan
M
Vockley
Jerry
J
McKinley
Laura
L
Kolls
Jay K
JK
Steele
Chad
C
D017088:AIDS-Related Opportunistic Infections / Q000276:immunology* / Q000517:prevention & control; D000256:Adenoviridae; D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D016867:Immunocompromised Host / Q000276:immunology*; D007127:Immunoglobulin Constant Regions / Q000235:genetics / Q000494:pharmacology*; D037181:Lectins, C-Type; D008168:Lung / Q000276:immunology / Q000382:microbiology; D016676:Macrophages, Alveolar / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000494:pharmacology*; D051379:Mice; D016513:Mice, SCID; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000494:pharmacology*; D045363:Pneumocystis carinii / Q000276:immunology*; D011020:Pneumonia, Pneumocystis / Q000276:immunology* / Q000628:therapy; D017452:Receptors, IgG / Q000819:agonists / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology; D047071:beta-Glucans / Q000276:immunology; D000099181:Dectin-1
D007127:Immunoglobulin Constant Regions; D037181:Lectins, C-Type; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; D047071:beta-Glucans; D000099181:Dectin-1; C485700:Fcgr3 protein, mouse