title: The Multifaceted Activity of the VirF Regulatory Protein in theShigellaLifestyle.
abstract: Shigellais a highly adapted human pathogen, mainly found in the developing world and causing a severe enteric syndrome. The highly sophisticated infectious strategy ofShigellabanks on the capacity to invade the intestinal epithelial barrier and cause its inflammatory destruction. The cellular pathogenesis and clinical presentation of shigellosis are the sum of the complex action of a large number of bacterial virulence factors mainly located on a large virulence plasmid (pINV). The expression of pINV genes is controlled by multiple environmental stimuli through a regulatory cascade involving proteins and sRNAs encoded by both the pINV and the chromosome. The primary regulator of the virulence phenotype is VirF, a DNA-binding protein belonging to the AraC family of transcriptional regulators. ThevirFgene, located on the pINV, is expressed only within the host, mainly in response to the temperature transition occurring when the bacterium transits from the outer environment to the intestinal milieu. VirF then acts as anti-H-NS protein and directly activates theicsAandvirBgenes, triggering the full expression of the invasion program ofShigella. In this review we will focus on the structure of VirF, on its sophisticated regulation, and on its role as major player in the path leading from the non-invasive to the invasive phenotype ofShigella. We will address also the involvement of VirF in mechanisms aimed at withstanding adverse conditions inside the host, indicating that this protein is emerging as a global regulator whose action is not limited to virulence systems. Finally, we will discuss recent observations conferring VirF the potential of a novel antibacterial target for shigellosis.
authors.affiliation: Dipartimento di Biologia e Biotecnologie C. Darwin, Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza Università di Roma Roma, Italy.
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Di Martino
authors.affiliation: Laboratorio di Genetica Molecolare e dei Microrganismi, Scuola di Bioscienze e Medicina Veterinaria, Università di Camerino Camerino, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Falconi
authors.affiliation: Istituto di Biologia e Patologia Molecolari, Consilglio Nazionale Delle Richerche Roma, Italy.
authors.forename: Gioacchino
authors.initials: G
authors.lastname: Micheli
authors.affiliation: Dipartimento di Biologia e Biotecnologie C. Darwin, Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza Università di Roma Roma, Italy.
authors.forename: Bianca
authors.initials: B
authors.lastname: Colonna
authors.affiliation: Dipartimento di Biologia e Biotecnologie C. Darwin, Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza Università di Roma Roma, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Prosseda
keywords: AraC proteins; DNA binding proteins; Shigella; VirF; antivirulence therapy; bacterial virulence; pathogenic E. coli; transcriptional regulators