What is the pathophysiology of virulence in Shigella infection?

Updated: Apr 03, 2018
  • Author: Jaya Sureshbabu, MBBS, MRCPCH(UK), MRCPI(Paeds), MRCPS(Glasg), DCH(Glasg); Chief Editor: Russell W Steele, MD  more...
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Virulence in Shigella species involves both chromosomal-coded and plasmid-coded genes. Virulent Shigella strains produce disease after invading the intestinal mucosa; the organism only rarely penetrates beyond the mucosa. [4]

The characteristic virulence trait is encoded on a large (220 kb) plasmid responsible for synthesis of polypeptides that cause cytotoxicity. Shigellae that lose the virulence plasmid are no longer pathogenic. Escherichia coli (E coli O157:H7) that harbor this plasmid clinically behave as Shigella bacteria. [5]

Siderophores, a group of plasmid-coded genes, control the acquisition of iron from host cells from its protein-bound state. In the extra intestinal phase of infection by gram-negative bacteria, iron becomes one of the major factors that limit further growth. This limitation occurs because most of the iron in human body is sequestered in hemoproteins (i.e., hemoglobin, myoglobin) or iron-chelating proteins involved in iron transport (transferrin and lactoferrin). Many bacteria can secrete iron chelating compounds, or siderophores, which chelate iron from the intestinal fluids and which bacteria then take up to obtain iron for its metabolic needs. These siderophores are under the control of plasmids and are tightly regulated by genes such that, under low iron conditions, expression of the siderophore system is high.

Regulatory genes control expression of virulence genes. Shiga toxin (Stx) is not essential for virulence of S dysenteriae type 1 but contributes to the severity of dysentery. Both plasmid-encoded virulence traits and chromosome-encoded factors are essential for full virulence of shigellae.

Regarding chromosomally encoded enterotoxin, many pathogenic features of Shigella infection are due to the production of potent cytotoxins known as Stx, a potent protein synthesis–inhibiting exotoxin. Shigella strains produce distinct enterotoxins. These are a family of cytotoxins that contain 2 major immunologically non–cross-reactive groups called Stx1 and Stx2. The homology sequences between Stx1 and Stx2 are 55% and 57% in subunits A and B, respectively.

These toxins are lethal to animals; enterotoxic to ligated rabbit intestinal segments; and cytotoxic for vero, HeLa, and some selected endothelial cells (human renal vascular endothelial cells) manifesting as diarrhea, dysentery, and hemolytic-uremic syndrome (HUS). [6] Stx1 is synthesized in significant amount by S dysenteriae serotype 1 and S flexneri 2a and E coli (Shigella toxin–producing E coli [ShET]). [7]

Stx1 and Stx2 are both encoded by a bacteriophage inserted into the chromosome. Stx1 increases inflammatory cytokine production by human macrophages, which, in turn, leads to a burst of interleukin (IL)-8. This could be relevant in recruiting neutrophils to the lamina propria of the intestine in hemorrhagic colitis and accounts for elevated levels of IL-8 in serum of patients with diarrhea-associated HUS.

Stxs have 2 subunits. Stx is transported into nucleoli. Stx nucleolar movement is carrier-dependent and energy-dependent. Subunit A is a 32-kD polypeptide that, when digested by trypsin, generates A1 with a 28-kD fragment and another small fragment, A2, which is 4 kD. A1 fraction acts like N -glycosidase; it removes single adenine residue from 28S rRNA of ribosome and inhibits protein synthesis. The A2 fraction is a pentamer polypeptide of 7.7-kD protein and is required to bind the A1 fraction to the B subunit. The main function of the B subunit is the binding of toxins to the cell surface receptor, typically globotriaosylceramide (Gb3), on the brush border of intestinal epithelial cells. [8]

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