Roles of Two-Component Signal Transduction Systems in Shigella Virulence

Abstract

Two-component signal transduction systems (TCSs) are widespread types of protein machinery, typically consisting of a histidine kinase membrane sensor and a cytoplasmic transcriptional regulator that can sense and respond to environmental signals. TCSs are responsible for modulating genes involved in a multitude of bacterial functions, including cell division, motility, differentiation, biofilm formation, antibiotic resistance, and virulence. Pathogenic bacteria exploit the capabilities of TCSs to reprogram gene expression according to the different niches they encounter during host infection. This review focuses on the role of TCSs in regulating the virulence phenotype of Shigella, an intracellular pathogen responsible for severe human enteric syndrome. The pathogenicity of Shigella is the result of the complex action of a wide number of virulence determinants located on the chromosome and on a large virulence plasmid. In particular, we will discuss how five TCSs, EnvZ/OmpR, CpxA/CpxR, ArcB/ArcA, PhoQ/PhoP, and EvgS/EvgA, contribute to linking environmental stimuli to the expression of genes related to virulence and fitness within the host. Considering the relevance of TCSs in the expression of virulence in pathogenic bacteria, the identification of drugs that inhibit TCS function may represent a promising approach to combat bacterial infections.

Keywords: Shigella virulence; bacterial regulation; stress response; two-component signal transduction systems.

Figure 1

Schematic representation of the two types of TCSs. (a) In Type A, the sensor domain at the N-terminal region of HK is followed by HAMP (a domain found in Histidine kinases, Adenyl cyclases, Methyl-accepting proteins, and Phosphatases), DHp (Dimerization and Histidine phosphotransfer domain), and CA (Catalytic and ATP-binding domain) at the C-terminal region. (b) In Type B, the sensor domain at the N-terminal region of the hybrid sensor is followed by PAS (Per-Arnt-Sim domain), DHp, CA, REC (Receiver domain), and HPt (Histidine Phosphotransfer domain) at the C-terminal region. RR consists of the REC domain (N-terminal) and ED (Effector domain) (C-terminal).

Figure 2

Role of TCS systems in the different steps of the invasive process of Shigella. (a) Shigella crosses the colonic epithelium via M cell translocation. (b) Shigella invades the resident macrophages, induces lysis of the phagolysosome, surviving the cell attack, and (c) escapes the macrophages by triggering inflammatory cell death (pyroptosis) with a consequent release of proinflammatory cytokines. (d) Shigella invades epithelial cells of colonic mucosa by stimulating macropinocytosis, induces vacuole lysis, multiplies in the cell cytosol, and (e) spreads to adjacent cells using actin-based motility. The involvement of TCS systems in the various steps is reported in the boxes.