Cellular Aspects of Shigella Pathogenesis: Focus on the Manipulation of Host Cell Processes

Abstract

Shigella is a Gram-negative bacterium that is responsible for shigellosis. Over the years, the study of Shigella has provided a greater understanding of how the host responds to bacterial infection, and how bacteria have evolved to effectively counter the host defenses. In this review, we provide an update on some of the most recent advances in our understanding of pivotal processes associated with Shigella infection, including the invasion into host cells, the metabolic changes that occur within the bacterium and the infected cell, cell-to-cell spread mechanisms, autophagy and membrane trafficking, inflammatory signaling and cell death. This recent progress sheds a new light into the mechanisms underlying Shigella pathogenesis, and also more generally provides deeper understanding of the complex interplay between host cells and bacterial pathogens in general.

Keywords: NLR; Nod1 signaling adaptor protein; Nod2 signaling adaptor protein; Shigella; autophagy; bacterial infections; innate immunity; toll-like receptors.

Figure 1

Distinct phases of invasion and autophagy targeting during Shigella infection. Shigella adheres to the basolateral surface of epithelial cells, forms a pore in the eukaryotic membrane, and delivers effector proteins to induce its uptake (Box 1). The first wave of autophagy targeting follows initial invasion and is mediated by recruitment of the autophagy machinery to the site of entry. The intracellular PRRs, NOD1 and NOD2, play a critical role through the recruitment of ATG16L1. Following escape from the entry vacuole, Shigella drive actin polymerization at one pole through IcsA-dependent recruitment of N-WASP and ARP2/3. This allows for intracellular motility. This process is countered by the host's attempt to trap bacteria in septin-derived cages that enables autophagy targeting. Once motile and free in the cytosol the host is unable to target Shigella to autophagy. Actin-based motility allows Shigella to spread from cell-cell, and it efficiently escapes into the second cell using a reactivated T3SS. This secondary invasion event allows for additional autophagy targeting. IcsB mutants that are less efficient at escape are more readily targeted by autophagy at this step.

Figure 2

Shigella infection induces metabolic changes in the host and the bacteria. Amino acid (AA) starvation is induced following bacterial infection, and this leads to numerous changes in the metabolism of the host cell including the induction of the integrated stress response (ISR) causing transcriptional reprogramming and formation of stress granules. The inhibition of mTOR signaling is also seen, with multiple downstream effects. Within Shigella, key cofactors such as iron need to be scavenged for essential survival processes. The tricarboxylic acid (TCA) cycle is less important than other processes such as fermentation. The Embden-Meyerhof-Parnas (EMP) pathway predominates the generation of pyruvate in comparison to the pentose-phosphate pathway (PPP) and the Entner-Doudoroff (ED) pathway.