THE CLASSICAL HEMOLYTIC-UREMIC SYNDROME - PATHOGENESIS UPDATE

The classical hemolytic uremic syndrome (HUS) and hemorrhagic colitis (HC) are uncommon, but characteristic complications of intestinal infe ction by verotoxin (VT) producing E. coli (VTEC). VTEC are transmitted directly by contaminated food or from person to person by the fecal-o ral route. They adhere tightly to the host's enterocytes by the aid of a 94 kD outer membrane protein (>>intimin<<) producing attaching and effacing lesions of the gut mucosa and causing watery or bloody diarrh ea. The lectin-like, pentameric B subunit of the toxin binds specifica lly to the glycolipid receptor (globotriaosylceramide, Gb3) of the tar get cells. Internalization of VT by ATP-dependent, receptor-mediated e ndocytosis leads to the inhibition of protein synthesis and subsequent cell death due to the endoRNAase activity of the A subunit. Systemic distribution of VT is hypothesized to account for the widespread lesio ns of HUS, but the mechanism that allows translocation of VT from the gut into the blood stream is not well understood. After intravenous in jection into rabbits, VT binds selectively to small blood vessels of t he intestinal mucosa and of the central nervous system, but not to glo merular capillaries. The thrombotic microangiopathy observed in target rabbit tissues closely resembles that seen in human HC and HUS. Gb3, which is abundant in human renal tissue, is not found in the rabbit ki dney. Recent experiments also show that tumor necrosis alpha (TNF-alph a) synergistically enhances VT mediated cytotoxicity of cultured vascu lar endothelial cells. One possible explanation is the cytokine-induce d increase of endothelial Gb3. It is hypothesized that the species- an d organ-specific expression of functional receptors on small vessel en dothelial cells determines the target site(s) for circulating VT and i ts specific clinical picture.