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 [ 3 H]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

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... um. 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. EXPERIMENTAL PROCEDURES Mice-Swiss Black SP-AϪ/Ϫ mice (a gift of J. Whitsett and T. Korfhagen) were developed from embryonic stem cells after disruption of the mouse SP-A gene by homologous recombination and maintained by breeding with Swiss Black mice, as previously described (7) . The SP-A null allele was bred into the C3H/HeN background through nine generations using a PCR-based genotyping strategy to track the neomycin locus of the gene-targeting cassette (8). All animals were housed in positively ventilated microisolator cages with automatic recirculat-