New Insights into How Yersinia pestis Adapts to Its Mammalian Host during Bubonic Plague

Abstract

Bubonic plague (a fatal, flea-transmitted disease) remains an international public health concern. Although our understanding of the pathogenesis of bubonic plague has improved significantly over the last few decades, researchers have still not been able to define the complete set of Y. pestis genes needed for disease or to characterize the mechanisms that enable infection. Here, we generated a library of Y. pestis mutants, each lacking one or more of the genes previously identified as being up-regulated in vivo. We then screened the library for attenuated virulence in rodent models of bubonic plague. Importantly, we tested mutants both individually and using a novel, “per-pool” screening method that we have developed. Our data showed that in addition to genes involved in physiological adaption and resistance to the stress generated by the host, several previously uncharacterized genes are required for virulence. One of these genes (ympt1.66c, which encodes a putative helicase) has been acquired by horizontal gene transfer. Deletion of ympt1.66c reduced Y. pestis' ability to spread to the lymph nodes draining the dermal inoculation site – probably because loss of this gene decreased the bacteria's ability to survive inside macrophages. Our results suggest that (i) intracellular survival during the early stage of infection is important for plague and (ii) horizontal gene transfer was crucial in the acquisition of this ability.

Functional and Structural Analysis of HicA3-HicB3, a Novel Toxin-Antitoxin System of Yersinia pestis

“…We suggested previously that hicB3 may be involved in plague pathogenesis (3). Our present results show that a Y. pestis ⌬hicA3B3 mutant is fully virulent; hence, the loss of virulence of the ⌬hicB3 mutant is due to inefficient in vivo growth caused by the activity of free HicA3 RNase, not to the lack of HicB3 as a regulator.…”

“…We reported previously that Y. pestis lacking ypo3369 is attenuated for virulence (3). ypo3369 is referred to as hicB3 by another research group, since its 135-aa product presents homology with the HicB antitoxin in the Escherichia coli HicA-HicB TAS (5).…”

“…Flea-borne plague leads to bubonic plague or (to a lesser extent) primary septicemic plague, whereas aerosol transmission produces pneumonia (2). To better understand the mechanisms responsible for disease production, we previously screened a library of Y. pestis deletion mutants for attenuated virulence in a rat model of bubonic plague (3). Each mutant in the library lacked one or more of the genes determined by comparative transcriptome analysis to be upregulated in vivo (4).…”

“…Each mutant in the library lacked one or more of the genes determined by comparative transcriptome analysis to be upregulated in vivo (4). One of the virulence-attenuated mutants lacked the uncharacterized ypo3369 gene (3). Although it had been suggested that ypo3369 (also referred to as hicB3) encoded an antitoxin from a toxin-antitoxin system (TAS) (5), the associated toxin gene had yet to be identified.…”

Inactivation of Peroxiredoxin 6 by the Pla Protease of Yersinia pestis

“…While the loss of Prdx6 results in increased ROS production during ALI/ARD, during infection with Y. pestis, the bacterial Yop-Ysc type III secretion system might otherwise serve as a mechanism to suppress ROS generation within the host, even in the absence of Prdx6. Based on gene expression data collected from rat buboes and infected macrophages, it has been shown that Y. pestis encounters ROS during the initial stage of infection but not later (58). Therefore, it remains possible that the cleavage of Prdx6 may affect the infection in ways not assessed here or that the impact may be masked by the activities of other Y. pestis virulence factors.…”