Surfactant Proteins A and D Inhibit the Growth of Gram-negative Bacteria by Increasing Membrane Permeability

J Clin Invest. 2003 May;111(10):1589-602. doi: 10.1172/JCI16889.


The pulmonary collectins, surfactant proteins A (SP-A) and D (SP-D), have been reported to bind lipopolysaccharide (LPS), opsonize microorganisms, and enhance the clearance of lung pathogens. In this study, we examined the effect of SP-A and SP-D on the growth and viability of Gram-negative bacteria. The pulmonary clearance of Escherichia coli K12 was reduced in SP-A-null mice and was increased in SP-D-overexpressing mice, compared with strain-matched wild-type controls. Purified SP-A and SP-D inhibited bacterial synthetic functions of several, but not all, strains of E. coli, Klebsiella pneumoniae, and Enterobacter aerogenes. In general, rough E. coli strains were more susceptible than smooth strains, and collectin-mediated growth inhibition was partially blocked by coincubation with rough LPS vesicles. Although both SP-A and SP-D agglutinated E. coli K12 in a calcium-dependent manner, microbial growth inhibition was independent of bacterial aggregation. At least part of the antimicrobial activity of SP-A and SP-D was localized to their C-terminal domains using truncated recombinant proteins. Incubation of E. coli K12 with SP-A or SP-D increased bacterial permeability. Deletion of the E. coli OmpA gene from a collectin-resistant smooth E. coli strain enhanced SP-A and SP-D-mediated growth inhibition. These data indicate that SP-A and SP-D are antimicrobial proteins that directly inhibit the proliferation of Gram-negative bacteria in a macrophage- and aggregation-independent manner by increasing the permeability of the microbial cell membrane.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Bacterial Outer Membrane Proteins / genetics
  • Bronchoalveolar Lavage Fluid / chemistry
  • Bronchoalveolar Lavage Fluid / microbiology
  • Cell Division / drug effects
  • Cell Membrane Permeability / drug effects*
  • Collectins / pharmacology
  • Dactinomycin / pharmacokinetics
  • Escherichia coli / drug effects
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Escherichia coli Infections / drug therapy
  • Escherichia coli Infections / metabolism
  • Fluorescent Dyes / pharmacokinetics
  • Genetic Predisposition to Disease
  • Gram-Negative Bacteria / drug effects*
  • Gram-Negative Bacteria / genetics
  • Gram-Negative Bacteria / metabolism
  • Humans
  • Mice
  • Mice, Inbred C3H
  • Mice, Knockout
  • Microbial Sensitivity Tests
  • Pulmonary Surfactant-Associated Protein A / deficiency
  • Pulmonary Surfactant-Associated Protein A / genetics
  • Pulmonary Surfactant-Associated Protein A / pharmacology*
  • Pulmonary Surfactant-Associated Protein D / biosynthesis
  • Pulmonary Surfactant-Associated Protein D / genetics
  • Pulmonary Surfactant-Associated Protein D / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Respiratory Tract Infections / drug therapy
  • Respiratory Tract Infections / metabolism


  • Bacterial Outer Membrane Proteins
  • Collectins
  • Fluorescent Dyes
  • Pulmonary Surfactant-Associated Protein A
  • Pulmonary Surfactant-Associated Protein D
  • OMPA outer membrane proteins
  • Dactinomycin