Macrophage-independent fungicidal action of the pulmonary collectins.
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.
McCormack
Francis X
FX
Veterans Affairs Medical Center, Cincinnati, Ohio 45220, USA. frank.mccormack@uc.edu
Gibbons
Reta
R
Ward
Susan R
SR
Kuzmenko
Alexander
A
Wu
Huixing
H
Deepe
George S
GS
D000362:Agar / Q000494:pharmacology; D000469:Alkaline Phosphatase / Q000378:metabolism; D000483:Alleles; D000818:Animals; D002455:Cell Division; D037222:Collectins / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006658:Histoplasma / Q000378:metabolism; D006801:Humans; D007962:Leukocytes / Q000382:microbiology; D008168:Lung / Q000166:cytology* / Q000378:metabolism / Q000382:microbiology*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D037662:Pulmonary Surfactant-Associated Protein A / Q000502:physiology; D037663:Pulmonary Surfactant-Associated Protein D / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000737:chemistry; D013154:Spleen / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism; D013997:Time Factors
D037222:Collectins; D037662:Pulmonary Surfactant-Associated Protein A; D037663:Pulmonary Surfactant-Associated Protein D; D011994:Recombinant Proteins; D000362:Agar; D000469:Alkaline Phosphatase