Shiga toxin

**Structure and mechanism** - AB5 toxin. The pentameric B subunit binds globotriaosylceramide (Gb3) receptors on target cells. Gb3 is abundant on renal glomerular endothelium, intestinal cells, and neurons. - The toxin is internalized by endocytosis and trafficked retrograde through the Golgi and ER to the cytosol. - The A subunit is an N-glycosidase. It removes a specific adenine from the 28S rRNA of the 60S ribosomal subunit. This blocks aminoacyl-tRNA binding, inhibits protein synthesis, and causes cell death. - Shiga toxin and Shiga-like toxins (Stx1, Stx2) share this mechanism. Stx2 is more strongly linked to HUS. - The genes are carried on a lambdoid bacteriophage (toxin transduction). Phage induction, for example by antibiotics, can increase toxin release.

**Organisms** - *Shigella dysenteriae* type 1 produces Shiga toxin. Other Shigella species cause dysentery through invasion and do not rely on Stx. - EHEC/STEC (O157:H7 and non-O157 serotypes) produce Shiga-like toxins (Stx1, Stx2). Unlike Shigella, they cause disease mainly through the toxin and do not invade the mucosa. - EHEC O157:H7 does not ferment sorbitol. It is detected on sorbitol-MacConkey agar (colorless colonies) and by Stx immunoassay or PCR. Sources include undercooked beef (hamburger), raw produce, and unpasteurized milk or juice. The infectious dose is low.

**Clinical significance** - Hemorrhagic colitis causes abdominal cramping and bloody diarrhea, usually without high fever. Stool shows few or no fecal leukocytes in EHEC. - Hemolytic uremic syndrome (HUS) is the classic triad of microangiopathic hemolytic anemia (schistocytes), thrombocytopenia, and acute kidney injury. It is most common in children under 5 and typically appears about 5–10 days after diarrhea begins. - Pathogenesis of HUS: Stx damages endothelial cells (especially renal glomerular), causing microthrombi, platelet consumption, and mechanical RBC shearing. - Labs in HUS: elevated BUN and creatinine, elevated LDH, low haptoglobin, and a normal PT/PTT. Normal coagulation distinguishes HUS from DIC. The Coombs test is negative. - Contrast with TTP: TTP has low ADAMTS13 activity and more neurologic symptoms and fever, and it is more common in adults.

**Management** - Supportive care: IV fluids and dialysis if needed. - Avoid antibiotics in EHEC infection. They may increase toxin release and the risk of HUS. - Avoid antimotility agents, which increase the risk of HUS. - Shigella infection is treated with antibiotics such as a fluoroquinolone, azithromycin, or ceftriaxone, depending on local resistance.

**High-yield comparisons** - Other toxins that inhibit protein synthesis: diphtheria toxin and *Pseudomonas* exotoxin A inactivate EF-2 through ADP-ribosylation. Shiga toxin acts on the 60S ribosome instead. - Shiga toxin is the only one of these that cleaves 28S rRNA. Ricin, a plant toxin, has the same mechanism. - Other AB5 toxins: cholera toxin and heat-labile ETEC toxin raise cAMP, and pertussis toxin is an AB5 toxin that blocks Gi.