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Infection and Immunity, April 2008, p. 1456-1464, Vol. 76, No. 4
0019-9567/08/$08.00+0     doi:10.1128/IAI.01197-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Capsular Antigen Fraction 1 and Pla Modulate the Susceptibility of Yersinia pestis to Pulmonary Antimicrobial Peptides Such as Cathelicidin

Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, Pennsylvania 19104

Received 30 August 2007/ Returned for modification 7 October 2007/ Accepted 6 January 2008

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°C; (ii) the antibacterial components of rBALF were small peptides (<10 kDa) that included two cationic antimicrobial peptides (CAMPs), the rat cathelicidin rCRAMP, and β-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 β-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.

Published ahead of print on 28 January 2008.

Editor: J. B. Bliska