Entamoeba histolytica cysteine proteinases with interleukin‐1 beta converting enzyme (ICE) activity cause intestinal inflammation and tissue damage in amoebiasis

Abstract

SummaryThe protozoan parasite Entamoeba histolytica causes intestinal inflammation and ulceration. Amoebic trophozoites activate the transcription factor NF-kB in human intestinal epithelial cells, initiating an inflammatory response programme with resultant damage to the intestinal tissue. Amoebic cysteine proteinases have been proposed as important virulence factors for amoebiasis. To test the role of amoebic cysteine proteinases in the pathogenesis of amoebic colitis, human intestinal xenografts in SCID mice were infected with E. histolytica trophozoites expressing an antisense message to ehcp5. The cysteine proteinase-deficient amoeba failed to induce intestinal epithelial cell production of the inflammatory cytokines interleukin (IL)-1B and IL-8, and caused significantly less gut inflammation and damage to the intestinal permeability barrier. The critical role of amoebic cysteine proteinases in human gut inflammation and tissue damage may be explained by our discovery that amoebic cysteine proteinases possess IL-1B converting enzyme (ICE) activity. This ICE activity could contribute to intestinal inflammation by activating human pIL-1B released by damaged intestinal cells. These results demonstrate for the first time that amoebic cysteine proteinases are a key virulence factor in amoebic colitis, and provide a novel mechanism for their activity.

Intestinal parasites: Associations with intestinal and systemic inflammation

“…On the other hand, pathogenic protozoa have shown to cause intestinal inflammation and tissue damage,17, 18 which have shown to exacerbate the systemic inflammatory process 19…”

Entamoeba histolytica - Pathogenic Protozoan of the Large Intestine in Humans

“…Stuck to the trophozoites mucosa secrete specific proteolytic enzymes such as hyaluronidase, cysteine proteinase, cathepsin B, which produce a local inflammatory reaction, congestion, degradation attacked by amoeba cells and facilitate trophozoites further invasion of the intestinal submucosa tissue [13,18,21,23]. Trophozoites of amoeba cause induction of the enzyme cyclooxygenase-2 (COX-2) in the lining of the bowel, leading to an increase in the secretion of prostaglandin E 2 (PGE 2 ), which contributes to the stimulation of the inflammatory process [24].…”

Mechanisms of Hepatocellular Dysfunction and Regeneration: Enzyme Inhibition by Nitroimidazole and Human Liver Regeneration

“…The antisense approach has been applied to E. histolytica cysteine proteinases and episomal expression of an antisense RNA to ehcp5 could reduce total amoebic proteinase activity by 80-90% [Ankri et al 1998]. To assess the role of E. histolytica cysteine proteinases in amoebiasis, in earlier study, human xenografts in SCID-HU-INT mice were infected with amoebic trophozoites expressing the ehcp5 antisense RNA(proteinase-deficient amoebae) or amoebic trophozoites containing the same plasmid without the antisense insert (the control group) [Zhang et al 2000]. Major findings were: 1. no obvious defect was apparent in the ability of cysteine-proteinase deficient amoebae to inhabit and survive within the colonic lumen; 2. post-24 h after infection, cysteine proteinase-deficient amoeba had, in contrast to the control group, failed to induce significant amounts of human IL-1 or IL-8 from infected intestine; 3. gut inflammation was also reduced in human intestine infected with cysteine-proteinase-deficient E. histolytica trophozoites; 4. control E. histolytica trophozoites damaged the intestinal permeability barrier at 24 h but there was only a minimal increase in intestinal permeability in human intestinal xenografts infected with cysteine-protease-deficient amoeba; 5. histological studies at 24 h, human xenografts infected with control amoebae showed damage to the colonic mucosa, invasion of amoebic trophozoites into submucosal tissues and neutrophil-predominant inflammation; 6. by contrast, xenografts infected with cysteine-proteinase-deficient amoebae showed less mucosal damage, almost no evidence for amoebic invasion into submucosal tissue and little inflammation.…”