Abstract
Yersinia pestis is the causative agent of plague. Previously we have isolated an attenuated Y. pestis transposon insertion mutant in which the pcm gene was disrupted. In the present study, we investigated the expression and the role of pcm locus genes in Y. pestis pathogenesis using a set of isogenic surE, pcm, nlpD and rpoS mutants of the fully virulent Kimberley53 strain. We show that in Y. pestis, nlpD expression is controlled from elements residing within the upstream genes surE and pcm. The NlpD lipoprotein is the only factor encoded from the pcm locus that is essential for Y. pestis virulence. A chromosomal deletion of the nlpD gene sequence resulted in a drastic reduction in virulence to an LD50 of at least 107 cfu for subcutaneous and airway routes of infection. The mutant was unable to colonize mouse organs following infection. The filamented morphology of the nlpD mutant indicates that NlpD is involved in cell separation; however, deletion of nlpD did not affect in vitro growth rate. Trans-complementation experiments with the Y. pestis nlpD gene restored virulence and all other phenotypic defects. Finally, we demonstrated that subcutaneous administration of the nlpD mutant could protect animals against bubonic and primary pneumonic plague. Taken together, these results demonstrate that Y. pestis NlpD is a novel virulence factor essential for the development of bubonic and pneumonic plague. Further, the nlpD mutant is superior to the EV76 prototype live vaccine strain in immunogenicity and in conferring effective protective immunity. Thus it could serve as a basis for a very potent live vaccine against bubonic and pneumonic plague.
Highlights
Yersinia pestis is the etiological agent of plague, which has caused millions of deaths in three world pandemics and is still a public health issue in some regions of the world
NlpD is an essential factor for the development of bubonic and pneumonic plague To test the contribution of SurE, Pcm, NlpD and RNA polymerase Sigma factor (RpoS) to Y. pestis pathogenesis, we evaluated the virulence of Kimberley53deletion mutants in mouse models of bubonic plague (s.c. infection) and pneumonic plague
Studies performed in the last decade with several Gram negative bacteria have demonstrated that the genomic region including the surE, pcm, nlpD and rpoS genes is important for survival under environmental stress conditions [18,36,43,44]
Summary
Yersinia pestis is the etiological agent of plague, which has caused millions of deaths in three world pandemics and is still a public health issue in some regions of the world. Primary pneumonic plague is less abundant in nature and results from inhalation of Y. pestis droplets or aerosols It is a rapidly progressing disease leading to high mortality rates in untreated patients and can spread from person to person [1]. The ability of Y. pestis to respond to the host environment and to overcome immune systems is attributed to the combined activity of multiple virulence mechanisms. The type III secretion system (TTSS) is essential for survival of the pathogen within the mammalian host environment This was demonstrated by the inability of Y. pestis strains devoid of the plasmid carrying the TTSS (pCD12) genes to colonize host tissues and to produce systemic disease following infection via both subcutaneous (s.c.) and airway routes [3,4,5,6]. These include the plasminogen activator factor, which is encoded on the pPCP1 plasmid [9,10,11]; the Yersiniabactin (Ybt) iron acquisition system, which is encoded within the high pathogenicity island [12,13]; the chromosomally encoded PurH involved in the synthesis of purines [4,14]; adenylate kinase, which is involved in nucleotide metabolism [15]; and the recently characterized YadBC [16]
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