Giardia duodenalis: Role of secreted molecules as virulent factors in the cytotoxic effect on epithelial cells.

During the course of giardiasis in humans and experimental models, G. duodenalis trophozoites express and secrete several proteins (ESPs) affecting structural, cellular and soluble components of the host intestinal milieu. These include the toxin-like molecules CRP136 and ESP58 that induce intestinal hyper-peristalsis. After the completion of the Giardia genome database and using up-to date transcriptomic and proteomic approaches, secreted 'virulence factors' have also been identified and experimentally characterized. This repertoire includes arginine deiminase (ADI) that competes for arginine, an important energy source for trophozoites, some high-cysteine membrane proteins (HCMPs) and VSP88, a versatile variant surface protein (VSP) that functions as an extracellular protease. Another giardial protein, enolase, moonlights as a metabolic enzyme that interacts with the fibrinolytic system and damages host epithelial cells. Other putative Giardia virulence factors are cysteine proteases that degrade multiple host components including mucin, villin, tight junction proteins, immunoglobulins, defensins and cytokines. One of these proteases, named giardipain-1, decreases transepithelial electrical resistance and induces apoptosis in epithelial cells. A putative role for tenascins, present in the Giardia's secretome, is interfering with the host epidermal growth factor. Based on the roles that these molecules play, drugs may be designed to interfere with their functions. This review presents a comprehensive description of secreted Giardia virulence factors. It further describes their cytotoxic mechanisms and roles in the pathophysiology of giardiasis, and then assesses their potential as targets for drug development.