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J. Biol. Chem., Vol. 278, Issue 38, 36250-36256, September 19, 2003

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Macrophage-independent Fungicidal Action of the Pulmonary Collectins^*

Francis X. McCormack  , Reta Gibbons ¶, Susan R. Ward ¶, Alexander Kuzmenko , Huixing Wu  and George S. Deepe, Jr. ¶

From the Veterans Affairs Medical Center, Cincinnati, Ohio 45220 and the Divisions of Pulmonary/Critical Care Medicine and ^¶Infectious Disease, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267

Histoplasma capsulatum (Hc) is a facultative intracellular fungal pathogen that causes acute and chronic pneumonia. In this study, we investigated the role of the pulmonary collectins, surfactant proteins (SP) A and D, in the clearance of Hc yeast from the lung. Exposure of yeast to either collectin induced a dose-dependent decrease in [³H]leucine incorporation by several strains of Hc. This decrement was attributed to killing of the collectin-exposed yeast since it failed to grow on agar medium. Exposure to SP-A or -D resulted in increased yeast permeability based on a leak of protein from the organism and enhanced access of an impermeant substrate to intracellular alkaline phosphatase. Inbred and outbred SP-A null (-/-) mice were modestly more susceptible to pulmonary infection with Hc than strain and age-matched SP-A (+/+) control mice. The increase in susceptibility was associated with a decrement in the number of CD8⁺ cells in the lungs of SP-A-/- mice. Neither SP-A nor SP-D inhibited the growth of macrophage-internalized Hc. We conclude that the SP-A and SP-D are antimicrobial proteins that directly inhibit the growth of Hc by increasing permeability of the organism and that Hc gains asylum from collectin-mediated killing by rapid entry into pulmonary macrophages.

Received for publication, March 26, 2003 , and in revised form, July 11, 2003.

^* This research was supported by National Institute of Health Grants AI 34361 and 42747 (to G. S. D.) and HL 61612 and 68861 (to F. X. M.), Department of Veterans Affairs Merit Reviews (to G. S. D. and F. X. M.), and a Research Enhancement Award Program award (to G. S. D. and F. X. M.). 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.

To whom correspondence should be addressed: Division of Pulmonary/Critical Care Medicine, 231 Albert Sabin Way, University of Cincinnati College of Medicine, Cincinnati, OH 45267. Tel.: 513-558-0480; Fax: 513-558-4858; E-mail: frank.mccormack{at}uc.edu.

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