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Infection and Immunity, April 2008, p. 1390-1409, Vol. 76, No. 4
0019-9567/08/$08.00+0     doi:10.1128/IAI.01529-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Braun Lipoprotein (Lpp) Contributes to Virulence of Yersiniae: Potential Role of Lpp in Inducing Bubonic and Pneumonic Plague

Jian Sha,^1, Stacy L. Agar,^1, Wallace B. Baze,² Juan P. Olano,^3,4 Amin A. Fadl,¹ Tatiana E. Erova,¹ Shaofei Wang,¹ Sheri M. Foltz,¹ Giovanni Suarez,¹ Vladimir L. Motin,^1,3,4 Sadhana Chauhan,¹ Gary R. Klimpel,^1,4 Johnny W. Peterson,^1,4 and Ashok K. Chopra^1,4*

Departments of Microbiology and Immunology,¹ Pathology,³ Sealy Center for Vaccine Development and Center for Biodefense and Emerging Infections, University of Texas Medical Branch, Galveston, Texas 77555-1070,⁴ Department of Veterinary Sciences, University of Texas, M. D. Anderson Cancer Center, Bastrop, Texas 78602²

Received 17 November 2007/ Returned for modification 4 January 2008/ Accepted 20 January 2008

Yersinia pestis evolved from Y. pseudotuberculosis to become the causative agent of bubonic and pneumonic plague. We identified a homolog of the Salmonella enterica serovar Typhimurium lipoprotein (lpp) gene in Yersinia species and prepared lpp gene deletion mutants of Y. pseudotuberculosis YPIII, Y. pestis KIM/D27 (pigmentation locus minus), and Y. pestis CO92 with reduced virulence. Mice injected via the intraperitoneal route with 5 x 10⁷ CFU of the lpp KIM/D27 mutant survived a month, even though this would have constituted a lethal dose for the parental KIM/D27 strain. Subsequently, these lpp KIM/D27-injected mice were solidly protected against an intranasally administered, highly virulent Y. pestis CO92 strain when it was given as five 50% lethal doses (LD₅₀). In a parallel study with the pneumonic plague mouse model, after 72 h postinfection, the lungs of animals infected with wild-type (WT) Y. pestis CO92 and given a subinhibitory dose of levofloxacin had acute inflammation, edema, and masses of bacteria, while the lung tissue appeared essentially normal in mice inoculated with the lpp mutant of CO92 and given the same dose of levofloxacin. Importantly, while WT Y. pestis CO92 could be detected in the bloodstreams and spleens of infected mice at 72 h postinfection, the lpp mutant of CO92 could not be detected in those organs. Furthermore, the levels of cytokines/chemokines detected in the sera were significantly lower in animals infected with the lpp mutant than in those infected with WT CO92. Additionally, the lpp mutant was more rapidly killed by macrophages than was the WT CO92 strain. These data provided evidence that the lpp mutants of yersiniae were significantly attenuated and could be useful tools in the development of new vaccines.

Published ahead of print on 28 January 2008.

Editor: S. R. Blanke

J.S. and S.L.A. contributed equally to the manuscript.

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