Braun Lipoprotein (Lpp) Contributes to Virulence of Yersiniae: Potential Role of Lpp in Inducing Bubonic and Pneumonic Plague

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Abstract
Yersinia pestisevolved fromY. pseudotuberculosisto become the causative agent of bubonic and pneumonic plague. We identified a homolog of theSalmonella entericaserovar Typhimurium lipoprotein (lpp) gene inYersiniaspecies and preparedlppgene deletion mutants ofY. pseudotuberculosisYPIII,Y. pestisKIM/D27 (pigmentation locus minus), andY. pestisCO92 with reduced virulence. Mice injected via the intraperitoneal route with 5 × 107CFU of the ΔlppKIM/D27 mutant survived a month, even though this would have constituted a lethal dose for the parental KIM/D27 strain. Subsequently, these ΔlppKIM/D27-injected mice were solidly protected against an intranasally administered, highly virulentY. pestisCO92 strain when it was given as five 50% lethal doses (LD50). In a parallel study with the pneumonic plague mouse model, after 72 h postinfection, the lungs of animals infected with wild-type (WT)Y. pestisCO92 and given a subinhibitory dose of levofloxacin had acute inflammation, edema, and masses of bacteria, while the lung tissue appeared essentially normal in mice inoculated with the Δlppmutant of CO92 and given the same dose of levofloxacin. Importantly, while WTY. pestisCO92 could be detected in the bloodstreams and spleens of infected mice at 72 h postinfection, the Δlppmutant of CO92 could not be detected in those organs. Furthermore, the levels of cytokines/chemokines detected in the sera were significantly lower in animals infected with the Δlppmutant than in those infected with WT CO92. Additionally, the Δlppmutant was more rapidly killed by macrophages than was the WT CO92 strain. These data provided evidence that the Δlppmutants of yersiniae were significantly attenuated and could be useful tools in the development of new vaccines.

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