Citation: Haidar-Ahmad, N.; Manigat, F.O.; Silué, N.; Pontier, S.M.; Campbell-Valois, F.-X. A Taleabout Shigella: Evolution, Plasmid, and Virulence. Microorganisms 2023, 11, 1709. https://doi.org/10.3390/ microorganisms11071709 Academic Editors: Francisco Ramos-Morales and Joaquín Bernal-Bayard Received: 9 June 2023 Revised: 23 June 2023 Accepted: 26 June 2023 Published: 30 June 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). microorganisms Review A Tale about Shigella: Evolution, Plasmid, and Virulence Nathaline Haidar-Ahmad 1,† , France Ourida Manigat 1,† , Navoun Silué 1,† , Stéphanie M. Pontier 2 and François-Xavier Campbell-Valois 1,3, * 1 Host-Microbe Interactions Laboratory, Centre for Chemical and Synthetic Biology, Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada; nhaid010@uottawa.ca (N.H.-A.); fmani073@uottawa.ca (F.O.M.); nsilu022@uottawa.ca (N.S.) 2 Centre de Recherche Santé Environnementale et Biodiversité de l’Outaouais (SEBO), CEGEP de l’Outaouais, Gatineau, QC J8Y 6M4, Canada; stephanie.pontier@cegepoutaouais.qc.ca 3 Centre for Infection, Immunity and Inflammation, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1N 6N5, Canada * Correspondence: fcampbel@uottawa.ca † These authors contributed equally to this work. 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: Shigella; Escherichia coli; pathogenesis; plasmid; type III secretion system; cell-to-cell spread; regulation of virulence genes; VirF; VirB; MxiE 1. Introduction Many gram-negative bacteria, such as Bordetella, Burkholderia, Citrobacter, Chlamydia, Escherichia, Pseudomonas, Rhizobium, Salmonella, Shigella, Xanthomonas, and Yersinia, interact with host cells using the syringe-shaped type III secretion system (T3SS) also known as the injectisome. This large proteinaceous complex injects substrate proteins into host cells to hijack them for the benefit of the bacteria that harbor it. Since 2015, spectacular progress has been made in describing its structure and function [1–9]. The T3SS is composed of the sorting platform that selects the protein substrates in the bacterial cytosol, the transmembrane needle complex that serves as a channel for the secretion of the substrates, the tip complex that triggers secretion upon sensing the physical contact with host cells, and the translocon that establishes the continuity between the needle complex and the host cytosol during the delivery of the substrates [7]. The Shigella flexneri T3SS has been one of the most extensively studied, providing us with an in-depth understanding of its role and function in pathogenesis (reviewed in [10–12]). In Shigella, the fate of the T3SS is tied to the large invasion plasmid that encodes it. Acquisition of this plasmid drove the evolution of Shigella spp. from Escherichia coli. This makes Shigella a powerful model to study the evolution of virulence and the interplay of the T3SS with its genome. Here, we focus on Microorganisms 2023, 11, 1709. https://doi.org/10.3390/microorganisms11071709 https://www.mdpi.com/journal/microorganisms