A new paradigm of bacteria-gut interplay brought through the study of Shigella

Abstract

Bacteria-gut epithelial interplay and the mucosal immune response are the most critical issues in determining the fate of bacterial infection and the severity of diseases. Shigella species (abbreviated here as Shigella), the causative agent of bacillary dysentery (shigellosis), are highly adapted human pathogens that are capable of invading and colonizing the intestinal epithelium, which results in severe inflammatory colitis. Shigella secrete a large and diverse number (more then 50) of effectors via the type III secretion system (TTSS) during infection, some of which are delivered into the surrounding bacterial space and some others into the host cell cytoplasm and nucleus. The delivered effectors mimic and usurp the host cellular functions, and modulate host cell signaling and immune response, thus playing pivotal roles in promoting bacterial infection and circumventing host defense systems. This article overviews the pathogenic characteristics of Shigella, and highlights current topics related to the bacterial infectious stratagem executed by the TTSS-secreted effectors. Though bacterial stratagems and the molecular mechanisms of infection vary greatly among pathogens, the current studies of Shigella provide a paradigm shift in bacterial pathogenesis.

Fig. 1

Kiyoshi Shiga (1871–1957). Photo provided courtesy of the Shibasaburo Kitasato Memorial Museum at the Kitasato Institute (Tokyo).

Fig. 2

A model for Shigella infection of intestinal epithelium. See the text for details.

Fig. 3

A model for Shigella-induced inflammatory response in epithelial cells and the bacterial down-regulation of the host inflammatory signals. During the multiplication of Shigella in epithelial cells, the peptidoglycan (PGN), including lipopolysaccharide (LPS), released from bacteria, can be recognized by the NOD1, which activates the downstream RICK and MAPK-mediated signal pathways, thus leading to the production of inflammatory chemokines, cytokines, and anti-microbial peptides. Intracellular Shigella delivers a subset of effectors, including IpaHs, OspF, and OspG via the TTSS, into the host cell cytoplasm and nucleus, enabling the effectors to target the host signaling pathways or factors involved in the inflammatory responses and dampen the inflammatory responses.

Fig. 4

A model of Shigella invasive mechanism for epithelial cells. Upon contact of Shigella to epithelial cells, the bacterium delivers several effectors (red circles) via the TTSS around the bacterial surface and into the host-cell cytoplasm. The bacterial effectors interact with the host target molecules to stimulate several signal transduction pathways capable of activating the Rac1-WAVE-Arp2/3 pathway, and induce local actin polymerization and protrude the membrane ruffles. See the text for details.

Fig. 5

The actin-dependent Shigella motility. (a) A confocal immunofluorescence image of the actin tail from one pole of the moving bacterium. (b) The machinery required for bacterial motility consists of VirG (a bacterial outer-membrane protein), N-WASP, Arp2/3 complex, Profilin, and Toca-1, and accumulates at one pole of the bacterium to polymerize actin.

Fig. 6

Autophagy affects the fate of bacterial colonization within host cells. Shigella, L. monocytogenes, and Burkholderia pseudomallei are capable of escaping from autophagy by exploiting the activities of IcsB, ActA, and BopA, respectively. Group A Streptoccus (GAS) internalized into the host cytoplasm is apprehended by autophagosomes and undergoes lysosomal degradation. M. tuberculosis, L. pneumophila, Brucella abortus, and Coxiella brunetti are sequestered by autophagosome-like membranes and undergo lysosomal degradation, if they cannot modulate the autophagy activity in macrophages.

Fig. 7

A model of Shigella evasion of autophagy (upper panel), and the strategy used by intracellular Shigella to escape from autophagy (lower panel). Shigella are capable of multiplying within the cytoplasm of epithelial cells and moving into adjacent epithelial cells. However, Shigella lacking the icsB gene, which encodes the IcsB effector, and acts as an anti-Atg5 binding factor for VirG, succumbs to autophagy and undergo lysosomal degradation. The upper right panel shows the VirG protein at one pole of bacterium, which is required for the actin-based bacterial motility.

Fig. 8

A model of L. monocytogenes escaping from autophagy recognition. L. monocytogenes disrupts the membrane enclosing bacterium by secreting LLO (Listeriolysin O), the pore-forming toxin, and disseminates into the host cell cytoplasm. During multiplication within the cytoplasm, L. monocytogenes expresses ActA over the bacterial surface, which recruits the Arp2/3 complex, Ena/VASP, and actin, thus disguising the bacterium against autophagic recognition, and allowing the bacterium to mediate actin polymerization and move within the host cells as well as into the neighboring cells. However, L. monocytogenes lacking ActA or expressing ActA mutants deficient in recruiting any of the host proteins become target for autophagic clearance, because the bacterium is ubiquitinated, which is followed by binding with p62 and LC3, thus allowing the bacterium to be apprehended by autophagosomes.

Fig. 9

(a) Shigella can directly access the cryptic progenitor cells in rabbit intestine. Shown is a rabbit intestinal tissue 12 h after inoculation with 2 × 10⁸ GFP-Shigella (green) stained with rhodamine-phalloidin (red) and TO-PRO3 (blue). (b) A model for Shigella strategy to cause cell cycle arrest via the interaction of the IpaB effector with Mad2L2. Once inside the epithelial progenitors, invaded bacterium delivers IpaB via TTSS, which interferes with the binding of Mad2L2 to Cdh1, leading to unscheduled activation of APC and subsequent Cyclin B1 degradation.

Fig. 10

A model of Shigella OspE targeting epithelial-cell ILK for the reinforcement of focal adhesion. Shigella deliver OspE via TTSS during multiplication within epithelial cells. This effector protein, OspE, reinforces epithelial adherence to the basement membrane by interacting with ILK. The interaction between OspE and ILK increases formation of focal adhesions and surface levels of β1-integrin, while suppressing phosphorylation of FAK and paxillin, thus dampening rapid turnover of focal adhesions, reducing cell motility and promoting cell adhesion to extracellular matrix.

Fig. 11

A model of Shigella strategy to antagonize the detachment of infected epithelial cells by delivering the OspE effectors. See the text for details.