Shigella

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Shigella spp. are transmitted by the fecal-oral route and enter the human body via the ingestion of contaminated food or water.

The bacteria are highly infectious, since as few as 10 to 100 microorganisms are sufficient to cause disease (61).

This low infectious dose can at least partially be attributed to the presence of effective acid resistance systems, which enable S. flexneri to survive the acidic environment in the stomach (88).

Furthermore, it was shown that Shigella spp. are able to downregulate the expression of antimicrobial peptides, which are important antibacterial effectors constantly released from the mucosal surfaces of the intestinal tract (118).

After passage through the stomach and small intestine, the bacteria reach the large intestine, where they establish an infection.

Most of the current knowledge on mechanisms underlying Shigella pathogenesis is derived from studies of S. flexneri. Infection with the invasive pathogen S. flexneri is a multistep process (Fig. ​(Fig.1).1).

To gain access to the intestinal mucosa, S. flexneri crosses the intestinal epithelium, which evolved as a physical and functional barrier to protect the body against the invasion of commensal and pathogenic bacteria (249).

In the initial phase of infection, S. flexneri apparently does not invade the epithelial barrier from the apical side but instead triggers its uptake into microfold cells (M cells) and is transcytosed across the epithelial layer (250, 325).

M cells are specialized epithelial cells (EC), which continuously sample particles from the gut lumen and deliver them to the underlying mucosal lymphoid tissue, where immune responses can be initiated (157).

The use of M cells as an entry port is consistent with the in vitro observation that S. flexneribarely interacts with the apical surface of polarized EC and enters these cells preferentially through the basolateral pol

After transcytosis, S. flexneri is released into an intraepithelial pocket, where the bacteria encounter resident macrophages that engulf and degrade incoming material.

S. flexneri ensures its survival in macrophages by rapidly inducing apoptosis (119, 347, 348). Macrophage cell death is accompanied by the release of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18 (256, 345).

Both cytokines are critical mediators of the acute and massive inflammatory response elicited by S. flexneri (Fig. ​(Fig.1).1).

While IL-1β signaling triggers the strong intestinal inflammation characteristic of shigellosis, IL-18 is involved in the generation of an effective antibacterial response (251, 256).

IL-18 activates natural killer (NK) cells and promotes the production of gamma interferon (IFN-γ), thus amplifying innate immune responses (148, 328).

However, the role of this cytokine in shigellosis has not been completely elucidated.

Once released from the dying macrophage, S. flexneri is able to invade EC from the basolateral side, escapes from the phagosome, and replicates in the cytoplasm (Fig. ​(Fig.1)1) (257).

Cytoplasmic S. flexneri moves by directed polymerization of actin, which allows the bacteria to spread to adjacent EC, avoiding exposure to extracellular components of the host immune defense (22, 174, 291).

Nevertheless, this strategy is a double-edged sword, as the invasion of EC also elicits a strong inflammatory response.

The Nod1-mediated intracellular surveillance system senses bacterial peptidoglycan fragments released by S. flexneriand activates nuclear factor κB (NF-κB), which triggers the up-regulation and secretion of the chemokine IL-8 (83, 211, 217, 252).

IL-8 mediates a massive recruitment of polymorphonuclear neutrophil leukocytes (PMN) to the site of infection (252, 286).

Furthermore, recent findings indicate that S. flexneri secretes effector proteins that actively shape the transcriptional response of infected EC to promote PMN migration (169, 344).

Even though massive inflammation promotes the initial infection by S. flexneri, recent reports provide evidence that bacteria secrete effectors that actively downregulate proinflammatory signals, perhaps to balance the severity of the inflammation on a level beneficial for the bacteria (14, 117, 131, 197).

It is becoming increasingly clear that S. flexneri skillfully exploits and evades the potentially harmful responses of the immune system