Yersinia pestis, an etiological agent of the acute diseases bubonic and pneumonic plague and one of the most devastating epidemic-causing bacteria experienced by mankind, is now classified as a re-emerging human pathogen by the WHO. The potential for contagion, lack of an effective vaccine, and emergence of multiple antibiotic- resistant strains place Y. pestis at the top of the U.S. select agent list as a potential bioterrorism agent. Our long-term goal is to elucidate molecular mechanisms underlying the acute bacterial infectious process of Y. pestis . The more immediate objective is to identify and evaluate new and existing antigens of Y. pestis to develop a new generation plague vaccine. The complete genome sequence of Y. pestis is now known.
Four aims are proposed.
In Aim 1 we will prepare a Braun/murein lipoprotein (lpp)-minus mutant of Y. pestis , based on our recent data that the patented Ipp isogenic mutants of Salmonella Typhimurium and of Y pseudotuberculosis are avirulent in mice and provide protection against challenge with the wild-type bacterium. We will examine these mutants for immunological responses in mice to develop a live attenuated Y. pestis vaccine or use Y. pseudotuberculosis as a carrier for Y. pestis antigens.
Aim 2 will identify differentially or exclusively expressed genes (potentially virulence-associated) of Y. pestis by genomics and proteomics to evaluate new antigens for use in a recombinant subunit plague vaccine.
Aim 3 will examine the virulence potential of selected in vivo-expressed genes of Y. pestis by developing isogenic mutants and evaluating them for lethality in a mouse model and assess selected antigens'ability to provide immunity against Y. pestis challenge.
Aim 4 will examine potential use of the Ipp-minus mutants of Y. pseudotuberculosis and S. Typhimurium as carriers to deliver Y. pestis antigens by expressing selected genes either from a plasmid under an inducible promoter and/or chromosome of attenuated Y. pseudotuberculosis/S. Typhimurium or by DMA vaccination. Alternatively, a vaccine strain of S. Typhi (Ty21a) could also be used. We believe these multiple approaches will identify candidate antigens for a use in a new, efficacious plague vaccine.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IMM-G (03))
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Mukhopadhyay, Suman
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University of Texas Medical Br Galveston
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Fitts, Eric C; Andersson, Jourdan A; Kirtley, Michelle L et al. (2016) New Insights into Autoinducer-2 Signaling as a Virulence Regulator in a Mouse Model of Pneumonic Plague. mSphere 1:
Andersson, Jourdan A; Fitts, Eric C; Kirtley, Michelle L et al. (2016) New Role for FDA-Approved Drugs in Combating Antibiotic-Resistant Bacteria. Antimicrob Agents Chemother 60:3717-29
Tiner, Bethany L; Sha, Jian; Ponnusamy, Duraisamy et al. (2015) Intramuscular Immunization of Mice with a Live-Attenuated Triple Mutant of Yersinia pestis CO92 Induces Robust Humoral and Cell-Mediated Immunity To Completely Protect Animals against Pneumonic Plague. Clin Vaccine Immunol 22:1255-68
van Lier, Christina J; Tiner, Bethany L; Chauhan, Sadhana et al. (2015) Further characterization of a highly attenuated Yersinia pestis CO92 mutant deleted for the genes encoding Braun lipoprotein and plasminogen activator protease in murine alveolar and primary human macrophages. Microb Pathog 80:27-38
Ponnusamy, Duraisamy; Fitts, Eric C; Sha, Jian et al. (2015) High-throughput, signature-tagged mutagenic approach to identify novel virulence factors of Yersinia pestis CO92 in a mouse model of infection. Infect Immun 83:2065-81
Tiner, Bethany L; Sha, Jian; Kirtley, Michelle L et al. (2015) Combinational deletion of three membrane protein-encoding genes highly attenuates yersinia pestis while retaining immunogenicity in a mouse model of pneumonic plague. Infect Immun 83:1318-38
Rosenzweig, Jason A; Ahmed, Sandeel; Eunson Jr, John et al. (2014) Low-shear force associated with modeled microgravity and spaceflight does not similarly impact the virulence of notable bacterial pathogens. Appl Microbiol Biotechnol 98:8797-807
van Lier, Christina J; Sha, Jian; Kirtley, Michelle L et al. (2014) Deletion of Braun lipoprotein and plasminogen-activating protease-encoding genes attenuates Yersinia pestis in mouse models of bubonic and pneumonic plague. Infect Immun 82:2485-503
Lawal, Abidat; Kirtley, Michelle L; van Lier, Christina J et al. (2013) The effects of modeled microgravity on growth kinetics, antibiotic susceptibility, cold growth, and the virulence potential of a Yersinia pestis ymoA-deficient mutant and its isogenic parental strain. Astrobiology 13:821-32
Tao, Pan; Mahalingam, Marthandan; Kirtley, Michelle L et al. (2013) Mutated and bacteriophage T4 nanoparticle arrayed F1-V immunogens from Yersinia pestis as next generation plague vaccines. PLoS Pathog 9:e1003495

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