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Deletion of Braun lipoprotein gene (lpp) and curing of plasmid pPCP1 dramatically alter the virulence of Yersinia pestis CO92 in a mouse model of pneumonic plague

¹ Department of Microbiology and Immunology, University of Texas Medical Branch (UTMB), Galveston, TX 77555, USA
² Department of Veterinary Sciences, University of Texas M. D. Anderson Cancer Center, Bastrop, TX 78602, USA
³ Sealy Center for Vaccine Development, UTMB, Galveston, TX 77555, USA
⁴ Center for Biodefense and Emerging Infectious Diseases, UTMB, Galveston, TX 77555, USA

Deletion of the murein (Braun) lipoprotein gene, lpp, attenuates the Yersinia pestis CO92 strain in mouse models of bubonic and pneumonic plague. In this report, we characterized the virulence of strains from which the plasminogen activating protease (pla)-encoding pPCP1 plasmid was cured from either the wild-type (WT) or the lpp mutant strain of Y. pestis CO92 in the mouse model of pneumonic infection. We noted a significantly increased survival rate in mice infected with the Y. pestis pPCP^–/lpp mutant strain up to a dose of 5000 LD₅₀. Additionally, mice challenged with the pPCP^–/lpp strain had substantially less tissue injury and a strong decrease in the levels of most cytokines and chemokines in tissue homogenates and sera when compared with the WT-infected group. Importantly, the Y. pestis pPCP^–/lpp mutant strain was detectable in high numbers in the livers and spleens of some of the infected mice. In the lungs of pPCP^–/lpp mutant-challenged animals, however, bacterial numbers dropped at 48 h after infection when compared with tissue homogenates from 1 h post-infection. Similarly, we noted that this mutant was unable to survive within murine macrophages in an in vitro assay, whereas survivability of the pPCP^– mutant within the macrophage environment was similar to that of the WT. Taken together, our data indicated that a significant and possibly synergistic attenuation in bacterial virulence occurred in a mouse model of pneumonic plague when both the lpp gene and the virulence plasmid pPCP1 encoding the pla gene were deleted from Y. pestis.

Correspondence
Ashok K. Chopra
achopra{at}utmb.edu

Three supplementary figures and six supplementary tables are available with the online version of this paper. The three supplementary figures show histopathology of mouse spleen and hearts following infection with wild-type, and various mutant strains of Y. pestis CO92 and type 3 secretion system-associated cytotoxicity in HeLa cells infected with wild-type and mutant Y. pestis CO92 strains. The six supplementary tables list cytokines and chemokines analysed in this study, and cytokine and chemokine levels in the lung, liver, spleen and heart homengenates and sera of mice 48 h p.i. with wild-type and mutant Y. pestis CO92 strains.