Cysteine proteinases and the pathogenesis of amebiasis

Abstract

Amebiasis is a major cause of morbidity and mortality throughout the tropical world. Entamoeba histolytica is now recognized as a separate species from the morphologically identical E. dispar, which cannot invade. Cysteine proteinases are a key virulence factor of E. histolytica and play a role in intestinal invasion by degrading the extracellular matrix and circumventing the host immune response through cleavage of secretory immunoglobulin A (sIgA), IgG, and activation of complement. Cysteine proteinases are encoded by at least seven genes, several of which are found in E. histolytica but not E. dispar. A number of new animal models, including the formation of liver abscesses in SCID mice and intestinal infection in human intestinal xenografts, have proven useful to confirm the critical role of cysteine proteinases in invasion. Detailed structural analysis of cysteine proteinases should provide further insights into their biochemical function and may facilitate the design of specific inhibitors which could be used as potential chemotherapeutic agents in the future.

FIG. 1

Model of cysteine proteinase expression during infection by E. histolytica and E. dispar. E. dispar expresses at least three cysteine proteinases (EdCP1, EdCP2, and EdCP3) but cannot invade. E. histolytica expresses at least five cysteine proteinases, ACP1, ACP2, ACP3, EhCP5, and EhCP112. Extracellular cysteine proteinases cleave sIgA, degrade the extracellular matrix, activate complement, and degrade IgG to circumvent the host immune response. Reprinted from reference with permission of the publisher.

FIG. 2

Model of the cysteine proteinases of Entamoeba. The relative sizes of the preenzyme, proenzyme, and mature enzymes are depicted. The ERFNIN motif of cathepsin L in the prosequence is shown, along with the three residues of the active site, cysteine (C), histidine (H), and asparagine (N). aa, amino acids.