Enhanced defense against Pneumocystis carinii mediated by a novel dectin-1 receptor Fc fusion protein

Academic Article

Abstract

  • 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 β-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 β-1,3 glucan linkages specifically and with high affinity (K = 2.03 × 10 M). Dectin-Fc enhances RAW264.7 macrophage recognition of the β-glucan containing particulate zymosan in an FcγRII- and FcγRIII-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 β-glucan with Dectin-Fc enhances host recognition and clearance of PC in the absence of B and T cells, and suggest that FcγR-based targeting of PC, via cell wall carbohydrate recognition, may promote resistance against PC pneumonia in the immunodeficient host. Copyright © 2007 by The American Association of Immunologists, Inc. + -7 D
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    Digital Object Identifier (doi)

    Author List

  • Rapaka RM; Goetzman ES; Zheng M; Vockley J; McKinley L; Kolls JK; Steele C
  • Start Page

  • 3702
  • End Page

  • 3712
  • Volume

  • 178
  • Issue

  • 6