A Tale about Shigella: Evolution, Plasmid, and Virulence

Abstract

Shigella spp. cause hundreds of millions of intestinal infections each year. They target the mucosa of the human colon and are an important model of intracellular bacterial pathogenesis. Shigella is a pathovar of Escherichia coli that is characterized by the presence of a large invasion plasmid, pINV, which encodes the characteristic type III secretion system and icsA used for cytosol invasion and cell-to-cell spread, respectively. First, we review recent advances in the genetic aspects of Shigella, shedding light on its evolutionary history within the E. coli lineage and its relationship to the acquisition of pINV. We then discuss recent insights into the processes that allow for the maintenance of pINV. Finally, we describe the role of the transcription activators VirF, VirB, and MxiE in the major virulence gene regulatory cascades that control the expression of the type III secretion system and icsA. This provides an opportunity to examine the interplay between these pINV-encoded transcriptional activators and numerous chromosome-encoded factors that modulate their activity. Finally, we discuss novel chromosomal genes icaR, icaT, and yccE that are regulated by MxiE. This review emphasizes the notion that Shigella and E. coli have walked the fine line between commensalism and pathogenesis for much of their history.

Keywords: Escherichia coli; MxiE; Shigella; VirB; VirF; cell-to-cell spread; pathogenesis; plasmid; regulation of virulence genes; type III secretion system.

Figure 1

Models for the emergence of Shigella from E. coli. (a) A tree illustrating the multiple pINV acquisition model. (b) A tree illustrating the single pINV acquisition model. These phylogenetic trees are qualitative and intended to be used for the sole purpose of illustrating the main difference between the two models in a straightforward manner. ShigA: Shigella from phylogroup A; ShigB1: Shigella from phylogroup B1; Shig1 and Shig2 as defined in the text and Table 1.

Figure 2

The invasion plasmid pINV. (a) pINV from S. flexneri strain M90T (accession number NC_024996.1). (b) pINV from S. sonnei strain 53 G (accession number NC_016833). The main features indicated in the outer rim are described in the legend. The open reading frames are represented by arrows and rectangles in the inner rims: the rims colored orange represent the top DNA strand, and the rims colored green represent the bottom DNA strand. The plasmid maps were created with Snapgene and Illustrator.

Figure 3

The major gene regulatory cascade in Shigella. (a) The signaling network regulating the expression of the invasive (T3SS) and cell-to-cell spread (icsA) traits in Shigella. It is centered around a vertical axis composed of transcription activators virF, virB, and mxiE and negatively regulated by hns at 30 °C. Events dominating at 30 °C, 37 °C, and when the injectisomes (inject.) are activated by contact with the HPM are represented as indicated in the legend. The transcription regulators and their terminal targets are written in black and magenta, respectively. (b) The virF, virB, and mxiE regulon. (c) The MxiE boxes of novel chromosomal genes icaR, icaT, yccE, and yhaBC compared with the consensus MxiE box of pINV-related members of the MxiE regulon.

Figure 4

Chromosome genes regulating the gene regulatory cascade. Chromosome genes and environmental cues modulating the expression of: (a) virF; (b) virB. The arrows toward virF and virB indicate transcriptional regulation. The arrows toward VirB indicate post-translational regulation. The arrows toward the black arrow joining virF-VirF or virB-VirB indicate post-transcriptional or translational regulation. Arrows toward VirB indicate post-translational regulation. The regulators and their terminal targets are written in black and magenta, respectively.