title: Natural Anti-Infective Pulmonary Proteins: In Vivo Cooperative Action of Surfactant Protein SP-A and the Lung Antimicrobial Peptide SP-BN.
abstract: The anionic antimicrobial peptide SP-B(N), derived from the N-terminal saposin-like domain of the surfactant protein (SP)-B proprotein, and SP-A are lung anti-infective proteins. SP-A-deficient mice are more susceptible than wild-type mice to lung infections, and bacterial killing is enhanced in transgenic mice overexpressing SP-B(N). Despite their potential anti-infective action, in vitro studies indicate that several microorganisms are resistant to SP-A and SP-B(N). In this study, we test the hypothesis that these proteins act synergistically or cooperatively to strengthen each other's microbicidal activity. The results indicate that the proteins acted synergistically in vitro against SP-A- and SP-B(N)-resistant capsulated Klebsiella pneumoniae (serotype K2) at neutral pH. SP-A and SP-B(N) were able to interact in solution (Kd = 0.4 μM), which enabled their binding to bacteria with which SP-A or SP-B(N) alone could not interact. In vivo, we found that treatment of K. pneumoniae-infected mice with SP-A and SP-B(N) conferred more protection against K. pneumoniae infection than each protein individually. SP-A/SP-B(N)-treated infected mice showed significant reduction of bacterial burden, enhanced neutrophil recruitment, and ameliorated lung histopathology with respect to untreated infected mice. In addition, the concentrations of inflammatory mediators in lung homogenates increased early in infection in contrast with the weak inflammatory response of untreated K. pneumoniae-infected mice. Finally, we found that therapeutic treatment with SP-A and SP-B(N) 6 or 24 h after bacterial challenge conferred significant protection against K. pneumoniae infection. These studies show novel anti-infective pathways that could drive development of new strategies against pulmonary infections.
authors.affiliation: Department of Biochemistry and Molecular Biology I, Complutense University of Madrid, 28040 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Instituto de Salud Carlos III, 28029 Madrid, Spain; and.
authors.forename: Juan Manuel
authors.initials: JM
authors.lastname: Coya
authors.affiliation: Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH 45229.
authors.forename: Henry T
authors.initials: HT
authors.lastname: Akinbi
authors.affiliation: Department of Biochemistry and Molecular Biology I, Complutense University of Madrid, 28040 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Instituto de Salud Carlos III, 28029 Madrid, Spain; and.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Sáenz
authors.affiliation: Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH 45229.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.affiliation: Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH 45229.
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Weaver
authors.affiliation: Department of Biochemistry and Molecular Biology I, Complutense University of Madrid, 28040 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Instituto de Salud Carlos III, 28029 Madrid, Spain; and ccasalsc@ucm.es.
authors.forename: Cristina
authors.initials: C
authors.lastname: Casals
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004357:Drug Synergism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007710:Klebsiella Infections / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000276:immunology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D011485:Protein Binding; D037662:Pulmonary Surfactant-Associated Protein A / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D037701:Pulmonary Surfactant-Associated Protein B / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D037661:Pulmonary Surfactant-Associated Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D016207:Cytokines; D037662:Pulmonary Surfactant-Associated Protein A; D037701:Pulmonary Surfactant-Associated Protein B; D037661:Pulmonary Surfactant-Associated Proteins; D011994:Recombinant Proteins