Pathogenesis of Shigella flexneri

Shigella flexneri causes bacillary dysentery, the symptoms of which include abdominal pain, diarrhea, fever, vomiting and blood or mucus in the stool. The bacteria are transmitted by the fecal-oral route, and through contaminated food and water. Once ingested, the bacteria survive the gastric environment of the stomach and move on to the large intestine. There, they attach to and penetrate the epithelial cells of the intestinal mucosa. After invasion, they multiply intracellularly and spread to neighboring epithelial cells, resulting in tissue destruction and characteristic pathology of shigellosis.

Entry of Shigella flexneri into Epithelial Cells
In order for S. flexneri to enter an epithelial cell, the bacterium must first adhere to its target cell. It is then internalized by a process which is similar to the mechanism of phagocytosis. Generally, the bacterium adheres to the membrane of the cell and is internalized via an endosome, which it subsequently lyses to gain access to the cytoplasm where multiplication occurs.

To aid its entry into the epithelial cell, the bacterial DNA encodes a number of plasmid and chromosomal proteins. These proteins are the invasion plasmid antigens (Ipa), surface presentation antigens (Spa), membrane excretion proteins (Mxi), and virulence proteins (Vir).

When the bacterium grows at 37^oC, the virulence protein VirF induces the expression of the VirB protein. The VirB protein then activates the ipa, mxi, and spa promoters leading to expression of the spa and mxi operons. This results in the synthesis and assembly of a protein complex called the Mxi-Spa translocon.  When the bacterium makes contact with the epithelial cell membrane, the translocon becomes activated and secretes the pre-synthesized Ipa proteins. IpaB, IpaC and IpaA associate to form a complex which interacts with the host epithelial cell membrane to induce a cascade of cellular signals which will lead to the internalization of the bacterium via an endosome. The Ipa proteins are also required for escape from the endosome.

Figure 2. Electron Micrograph of Shigella in a membrane-enclosed endosome of an epithelial cell

Intracellular and Intercellular Spread
Extracellular S. flexneri cells are nonmotile, but intracellular bacteria move to occupy the entire cytoplasm of the infected cell, and they are able to spread between cells. The genes necessary for intracellular and intercellular spreading are virG (icsA) and icsB.

After entry into the cell, intracellular movement occurs if the bacterium expresses both an Olm ("organelle-like movement") phenotype and an alternative Ics phenotype. The expression the Olm phenotype allows the bacteria to "slide" along actin stress cables inside the host cell, while the expression of the Ics phenotype allows the bacteria to "spread" or infect adjacent cells.

Specifically, movement of S. flexneri between adjacent cells is mediated via the product of the virG (icsA) gene. The icsA gene elicits actin polymerization at the poles of the bacteria and induces the formation of protrusions. In some instances, these tightly packed actin filaments appear to form a cylinder. The bacteria in the protrusions can move through the host cell and penetrate into an adjacent cell without coming in contact with the extracellular medium where they would be rendered nonmotile.

The mxiG gene is required for Ipa protein secretion, and is also essential for entry. This gene and others in the Mxi-Spa translocon are also required for intercellular dissemination.

Pathological Effects
Following host epithelial cell invasion and penetration of the colonic mucosa, Shigella infection is characterized by degeneration of the epithelium and inflammation of the lamina propria. This results in desquamation and ulceration of the mucosa, and subsequent leakage of blood, inflammatory elements and mucus into the intestinal lumen. Patients suffering from Shigella infection will therefore pass frequent, scanty, dysenteric stool mixed with blood and mucus, since, under these conditions, the absorption of water by the colon is inhibited. This is in opposition to the diarrheal symptoms seen in patients suffering from extensive Shigella colitis, and the pathologic basis for this is unknown. It is possible that prostaglandin interactions induced by the inflammatory response to bacterial invasion contribute to diarrhea in patients with Shigella colitis.