title: Capsular antigen fraction 1 and Pla modulate the susceptibility of Yersinia pestis to pulmonary antimicrobial peptides such as cathelicidin.
abstract: Inhaled Yersinia pestis produces a severe primary pneumonia known as pneumonic plague, which is contagious and highly lethal to humans and animals. In this study, we first determined the susceptibility of Y. pestis KIM6 to antimicrobial molecules of the airways. We found that (i) rat bronchoalveolar lavage fluid (rBALF) effectively killed KIM6 cells growing at 37 degrees C; (ii) the antibacterial components of rBALF were small peptides (<10 kDa) that included two cationic antimicrobial peptides (CAMPs), the rat cathelicidin rCRAMP, and beta-defensin RBD-1; (iii) the human cathelicidin LL-37 killed KIM6 cells as well as rBALF did; and (iv) the bactericidal property of LL-37 was synergistically amplified by human beta-defensin 1, another constitutively expressed pulmonary CAMP. Second, the effects of three major surface proteins of Y. pestis, namely, the capsular antigen fraction 1 (F1), the pH 6 antigen (Psa fimbriae), and the outer membrane protease Pla, on the bactericidal effect of the antimicrobial rBALF peptides was determined with corresponding deletion mutants. We showed that (i) a Y. pestis psa mutant was only slightly more susceptible to rBALF than the parental KIM6 strain, (ii) a caf (F1 gene) mutant and a caf psa mutant were resistant to rBALF or LL-37, (iii) a caf pla mutant was as susceptible to the effect of rBALF or LL-37 as KIM6 was (caf+ pla+), and (iv) only the single caf mutant (pla+), but not KIM6 or the caf pla double mutant, degraded LL-37. The activity of Pla toward LL-37 was confirmed with pla mutants carrying a single-residue substitution affecting plasminogen cleavage. Taken together, our data indicated that Pla might act as a virulence factor not only by processing plasminogen but also by inactivating CAMPs, particularly when F1 is not expressed.
authors.affiliation: Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104, USA.
authors.forename: Estela M
authors.initials: EM
authors.lastname: Galván
authors.forename: Melissa A S
authors.initials: MA
authors.lastname: Lasaro
authors.forename: Dieter M
authors.initials: DM
authors.lastname: Schifferli
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology*; D016667:Bacterial Capsules / Q000378:metabolism*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D054804:Cathelicidins; D006801:Humans; D009154:Mutation; D010960:Plasminogen Activators / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015010:Yersinia pestis / Q000187:drug effects* / Q000378:metabolism*; D023083:beta-Defensins / Q000494:pharmacology
chemical_list: D023181:Antimicrobial Cationic Peptides; D001426:Bacterial Proteins; D054804:Cathelicidins; C406407:DEFB1 protein, human; D023083:beta-Defensins; C086725:caf1 protein, Yersinia pestis; C078140:Pla protease, Yersinia pestis; D010960:Plasminogen Activators