Abstract

We showed recently that the live-attenuated Δlpp ΔmsbB Δail and Δlpp ΔmsbB::ailL2 mutants of Yersinia pestis CO92 provided short-term protection to mice against developing subsequent lethal pneumonic plague. These mutants were either deleted for genes encoding Braun lipoprotein (Lpp), an acetyltransferase (MsbB) and the attachment invasion locus (Ail) (Δlpp ΔmsbB Δail) or contained a modified version of the ail gene with diminished virulence (Δlpp ΔmsbB::ailL2). Here, long-term immune responses were first examined after intramuscular immunisation of mice with the above-mentioned mutants, as well as the newly constructed Δlpp ΔmsbB Δpla mutant, deleted for the plasminogen-activator protease (pla) gene instead of ail. Y. pestis-specific IgG levels peaked between day 35 and 56 in the mutant-immunised mice and were sustained until the last tested day 112. Splenic memory B cells peaked earlier (day 42) before declining in the Δlpp ΔmsbB::ailL2 mutant-immunised mice while being sustained for 63 days in the Δlpp ΔmsbB Δail and Δlpp ΔmsbB Δpla mutant-immunised mice. Splenic CD4+ T cells increased in all immunised mice by day 42 with differential cytokine production among the immunised groups. On day 120, immunised mice were exposed intranasally to wild-type (WT) CO92, and 80–100% survived pneumonic challenge. Mice immunised with the above-mentioned three mutants had increased innate as well as CD4+ responses immediately after WT CO92 exposure, and coupled with sustained antibody production, indicated the role of both arms of the immune response in protection. Likewise, rats vaccinated with either Δlpp ΔmsbB Δail or the Δlpp ΔmsbB Δpla mutant also developed long-term humoral and cell-mediated immune responses to provide 100% protection against developing pneumonic plague. On the basis of the attenuated phenotype, the Δlpp ΔmsbB Δail mutant was recently excluded from the Centers for Disease Control and Prevention select agent list.

Highlights

  • There has been a rise in the number of human plague cases globally resulting in the categorisation of Yersinia pestis, the aetiological agent of the highly fatal pneumonic plague, as a reemerging pathogen by the World Health Organization.[1]

  • On day 42, mice immunised with Δlpp ΔmsbB::ailL2, Attenuation in virulence of the newly generated Δlpp ΔmsbB Δpla mutant of Y. pestis CO92

  • The CD4+ population was 26.5 and 28.4% in mice immunised with Δlpp ΔmsbB::ailL2 and Δlpp ΔmsbB Δpla mutants, respectively (Figure 4a)

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Summary

Introduction

There has been a rise in the number of human plague cases globally resulting in the categorisation of Yersinia pestis, the aetiological agent of the highly fatal pneumonic plague, as a reemerging pathogen by the World Health Organization.[1] The progression of pneumonic plague is very rapid after first appearance of the symptoms in humans, and the case fatality rate approaches 100%, if the antimicrobial treatment is delayed.[2,3,4]. Live-attenuated vaccines promote both humoral- and cellmediated immune responses making them the optimal option to protect humans against pneumonic plague.[5,8] The various liveattenuated Y. pestis EV76 vaccine strains, which lack the pigmentation locus (pgm) required for iron acquisition, have been used in plague endemic parts of the world due to vaccine strains’ ability to provide protection against both bubonic and pneumonic plague.[5]

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