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Earlier, we reported the identification of new virulence factors/mechanisms of  Yersinia pestis  using an  in vivo  signature-tagged mutagenesis (STM) screening approach. From this screen, the role of  rbsA , which encodes an ATP-binding protein of ribose transport system, and  vasK , an essential component of the type VI secretion system (T6SS), were evaluated in mouse models of plague and confirmed to be important during  Y. pestis  infection. However, many of the identified genes from the screen remained uncharacterized. In this study, in-frame deletion mutants of  ypo0815, ypo2884, ypo3614-3168 (cyoABCDE) , and  ypo1119-1120 , identified from the STM screen, were generated. While  ypo0815  codes for a general secretion pathway protein E (GspE) of the T2SS, the  ypo2884 -encoded protein has homology to the βγ crystallin superfamily,  cyoABCDE  codes for the cytochrome o oxidase operon, and the  ypo1119-1120  genes are within the Tol-Pal system which has multiple functions. Additionally, as our STM screen identified three T6SS-associated genes, and, based on  in silico  analysis, six T6SS clusters and multiple homologs of the T6SS effector hemolysin-coregulated protein (Hcp) exist in  Y. pestis  CO92, we also targeted these T6SS clusters and effectors for generating deletion mutants. These deletion mutant strains exhibited varying levels of attenuation (up to 100%), in bubonic or pneumonic murine infection models. The attenuation could be further augmented by generation of combinatorial deletion mutants, namely Δ lpp Δ ypo0815 , Δ lpp Δ ypo2884 , Δ lpp Δ cyoABCDE , Δ vasK Δ hcp6 , and Δ ypo2720-2733 Δ hcp3 . We earlier showed that deletion of the  lpp  gene, which encodes Braun lipoprotein (Lpp) and activates Toll-like receptor-2, reduced virulence of  Y. pestis  CO92 in murine models of bubonic and pneumonic plague. The surviving mice infected with Δ lpp Δ cyoABCDE , Δ vasK Δ hcp6 , and Δ ypo2720-2733 Δ hcp3  mutant strains were 55–100% protected upon subsequent re-challenge with wild-type CO92 in a pneumonic model. Further, evaluation of the attenuated T6SS mutant strains  in vitro  revealed significant alterations in phagocytosis, intracellular survival in murine macrophages, and their ability to induce cytotoxic effects on macrophages. The results reported here provide further evidence of the utility of the STM screening approach for the identification of novel virulence factors and to possibly target such genes for the development of novel live-attenuated vaccine candidates for plague.

Identification of New Virulence Factors and Vaccine Candidates for Yersinia pestis