| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* Department of Pediatrics, Division of Pulmonary Medicine, Allergy, and Immunology and Division of Medical Genetics, Children’s Hospital of Pittsburgh, Pittsburgh, PA 15213; and
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261
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 
-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 -1,3 glucan linkages specifically and with high affinity (KD = 2.03 x 10–7 M). Dectin-Fc enhances RAW264.7 macrophage recognition of the -glucan containing particulate zymosan in an Fc
RII- and FcRIII-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 -glucan with Dectin-Fc enhances host recognition and clearance of PC in the absence of B and T cells, and suggest that FcR-based targeting of PC, via cell wall carbohydrate recognition, may promote resistance against PC pneumonia in the immunodeficient host.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants 5R01HL061271-08 and 5P01HL076100-030002 (to J.K.K.), 5R01HL080317-02 (to C.S.), and F30ES015413-01 (to R.R.R.).
2 Address correspondence and reprint requests to Dr. Chad Steele, Children’s Hospital of Pittsburgh, 3460 Fifth Avenue, Pittsburgh, PA 15213. E-mail address: chad.steele{at}chp.edu
3 Abbreviations used in this paper: PC, Pneumocystis carinii; HAART, highly active antiretroviral therapy; TMB, tetramethylbenzidine; MFI, mean fluorescence intensity; BALF, bronchoalveolar lavage fluid; LDH, lactate dehydrogenase; CRD, carbohydrate recognition domain; PAMP, pathogen-associated molecular pattern; SP-D, surfactant protein D; CH, constant heavy.
This article has been cited by other articles:
|
|
 |
|
  P. E. Mattila, A. E. Metz, R. R. Rapaka, L. D. Bauer, and C. Steele Dectin-1 Fc Targeting of Aspergillus fumigatus Beta-Glucans Augments Innate Defense against Invasive Pulmonary Aspergillosis Antimicrob. Agents Chemother., March 1, 2008; 52(3): 1171 - 1172. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
