New virulence mechanisms in Yersinia pestis, the plague (Black Death)-causing bacterium: A re-emerging and bioterror pathogen

Yersinia pestis evolved from Y. pseudotuberculosis to become the causative agent of bubonic and pneumonic plague. Y. pestis is also a category A select agent based on its potential use as a biological weapon. Currently, there is no vaccine licensed in the United States for use against Y. pestis so continued research on understanding the pathogenesis of Y. pestis and identifying new virulence factors is warranted. Although the natural route of primary infection with Y. pestis results in bubonic plague in humans, it is commonly thought that aerosolized Y. pestis will be utilized during a biowarfare attack. Therefore, the purpose of this work was two-fold: to assess the changes in virulence attributable to the deletion of a chromosomal element and a virulence plasmid; and to investigate disease progression following aerosolization of Y. pestis in two animal models. First, we characterized Y. pestis strains lacking murein, or Braun, lipoprotein (Lpp), an outer membrane protein conserved within the Enterobacteriaceae family. We then cured wild-type and ∆lpp mutant strains of virulent Y. pestis CO92 of one of the virulence plasmids, pPCP1, and assessed how these deletions attenuated the bacterium. 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 CO92. \r\nThe second half of this work focused on characterizing the dynamics of pneumonic infection following aerosolization of Y. pestis CO92 strain in both the mouse and rat models of infection. We exposed mice and rats in a whole-body Madison chamber to various doses of Y. pestis CO92 aerosolized by a Collison nebulizer and determined the LD50 dose, bacterial dissemination, cytokine/chemokine production, and tissue damage over a 72-h course of infection. Plague in mice and rats mimics disease in humans and understanding disease progression in these models will facilitate a better understanding of disease in humans.\r\n

Name thesis:degree_name

PhD

Level thesis:degree_level

Doctoral

Grantor

The University of Texas Medical Branch

Year dc:date.issued

2009

Author dc:creator

• Stacy Leona Agar

Advisor dc:contributor.advisor

• Ashok K. Chopra

Committee members dc:contributor.committeemember

• Wallace Baze
• Vladimir Motin
• Johnny W. Peterson
• Janice J. Endsley

• Yersinia pestis
• virulence
• plague
• bioterror

Statement dc:rights

• Copyright © is held by the author. Presentation of this material on the TDL web site by The University of Texas Medical Branch at Galveston was made possible under a limited license grant from the author who has retained all copyrights in the works.

Language dc:language.iso

eng

Dc Identifier Other

etd-04102009-214923

OAI identifier oai:identifier

oai:utmb-ir.tdl.org:2152.3/96