Deletion of Braun Lipoprotein and Plasminogen-Activating Protease-Encoding Genes Attenuates Yersinia pestis in Mouse Models of Bubonic and Pneumonic Plague
| Autor: | Yingzi Cong, Michelle L. Kirtley, Jian Sha, Bethany L. Tiner, Anthony T. Cao, Vsevolod L. Popov, Tatiana E. Erova, Christina J. van Lier, Ashok K. Chopra, Wallace B. Baze, Elena V. Kozlova |
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| Rok vydání: | 2014 |
| Předmět: |
Pneumonic plague
Yersinia pestis Lipoproteins Immunology Colony Count Microbial Biology Plague (disease) Microbiology Proinflammatory cytokine Mice Plasminogen Activators Immune system Antigen Immunity medicine Animals Analysis of Variance Plague Virulence Macrophages Gene Expression Regulation Bacterial medicine.disease biology.organism_classification Antibodies Bacterial Molecular Pathogenesis Virology Disease Models Animal Infectious Diseases Humoral immunity Cytokines Female Parasitology Chemokines Gene Deletion |
| Zdroj: | Infection and Immunity. 82:2485-2503 |
| ISSN: | 1098-5522 0019-9567 |
| DOI: | 10.1128/iai.01595-13 |
| Popis: | Currently, there is no FDA-approved vaccine against Yersinia pestis , the causative agent of bubonic and pneumonic plague. Since both humoral immunity and cell-mediated immunity are essential in providing the host with protection against plague, we developed a live-attenuated vaccine strain by deleting the Braun lipoprotein ( lpp ) and plasminogen-activating protease ( pla ) genes from Y. pestis CO92. The Δ lpp Δ pla double isogenic mutant was highly attenuated in evoking both bubonic and pneumonic plague in a mouse model. Further, animals immunized with the mutant by either the intranasal or the subcutaneous route were significantly protected from developing subsequent pneumonic plague. In mice, the mutant poorly disseminated to peripheral organs and the production of proinflammatory cytokines concurrently decreased. Histopathologically, reduced damage to the lungs and livers of mice infected with the Δ lpp Δ pla double mutant compared to the level of damage in wild-type (WT) CO92-challenged animals was observed. The Δ lpp Δ pla mutant-immunized mice elicited a humoral immune response to the WT bacterium, as well as to CO92-specific antigens. Moreover, T cells from mutant-immunized animals exhibited significantly higher proliferative responses, when stimulated ex vivo with heat-killed WT CO92 antigens, than mice immunized with the same sublethal dose of WT CO92. Likewise, T cells from the mutant-immunized mice produced more gamma interferon (IFN-γ) and interleukin-4. These animals had an increasing number of tumor necrosis factor alpha (TNF-α)-producing CD4 + and CD8 + T cells than WT CO92-infected mice. These data emphasize the role of TNF-α and IFN-γ in protecting mice against pneumonic plague. Overall, our studies provide evidence that deletion of the lpp and pla genes acts synergistically in protecting animals against pneumonic plague, and we have demonstrated an immunological basis for this protection. |
| Databáze: | OpenAIRE |
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