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Infection and Immunity, July 2009, p. 2783-2794, Vol. 77, No. 7
0019-9567/09/$08.00+0 doi:10.1128/IAI.00088-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Surfactant Protein D Increases Phagocytosis of Hypocapsular Cryptococcus neoformans by Murine Macrophages and Enhances Fungal Survival
,
Scarlett Geunes-Boyer,1
Timothy N. Oliver,1
Guilhem Janbon,5
Jennifer K. Lodge,4
Joseph Heitman,2,3
John R. Perfect,3 and
Jo Rae Wright1*
Departments of Cell Biology,1 Molecular Genetics and Microbiology,2 Medicine, Duke University Medical Center, Durham, North Carolina 27710,3 Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, Missouri 63104,4 Institut Pasteur, Unité des Aspergillus, F-75015 Paris, France5
Received 22 January 2009/ Returned for modification 24 February 2009/ Accepted 3 May 2009
Cryptococcus neoformans is a facultative intracellular opportunistic pathogen and the leading cause of fungal meningitis in humans. In the absence of a protective cellular immune response, the inhalation of C. neoformans cells or spores results in pulmonary infection. C. neoformans cells produce a polysaccharide capsule composed predominantly of glucuronoxylomannan, which constitutes approximately 90% of the capsular material. In the lungs, surfactant protein A (SP-A) and SP-D contribute to immune defense by facilitating the aggregation, uptake, and killing of many microorganisms by phagocytic cells. We hypothesized that SP-D plays a role in C. neoformans pathogenesis by binding to and enhancing the phagocytosis of the yeast. Here, the abilities of SP-D to bind to and facilitate the phagocytosis and survival of the wild-type encapsulated strain H99 and the cap59
mutant hypocapsular strain are assessed. SP-D binding to cap59 mutant cells was approximately sixfold greater than binding to wild-type cells. SP-D enhanced the phagocytosis of cap59 cells by approximately fourfold in vitro. To investigate SP-D binding in vivo, SP-D–/– mice were intranasally inoculated with Alexa Fluor 488-labeled cap59 or H99 cells. By confocal microscopy, a greater number of phagocytosed C. neoformans cells in wild-type mice than in SP-D–/– mice was observed, consistent with in vitro data. Interestingly, SP-D protected C. neoformans cells against macrophage-mediated defense mechanisms in vitro, as demonstrated by an analysis of fungal viability using a CFU assay. These findings provide evidence that C. neoformans subverts host defense mechanisms involving surfactant, establishing a novel virulence paradigm that may be targeted for therapy.
* Corresponding author. Mailing address: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710. Phone: (919) 684-3187. Fax: (919) 681-0377. E-mail: j.wright{at}cellbio.duke.edu
Published ahead of print on 18 May 2009.
Supplemental material for this article may be found at http://iai.asm.org/.
Infection and Immunity, July 2009, p. 2783-2794, Vol. 77, No. 7
0019-9567/09/$08.00+0 doi:10.1128/IAI.00088-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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