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Published on: June 12, 2014
Extracellular Cysteine Proteases of Key Intestinal Protozoan Pathogens-Factors Linked to Virulence and Pathogenicity
Raúl Argüello-García1, Julio César Carrero2, M Guadalupe Ortega-Pierres1
1Departamento de Genética y Biología Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México City 07360, Mexico.
Abstract:
Intestinal diseases caused by protistan parasites of the genera Giardia (giardiasis), Entamoeba (amoebiasis), Cryptosporidium (cryptosporidiosis) and Blastocystis (blastocystosis) represent a major burden in human and animal populations worldwide due to the severity of diarrhea and/or inflammation in susceptible hosts. These pathogens interact with epithelial cells, promoting increased paracellular permeability and enterocyte cell death (mainly apoptosis), which precede physiological and immunological disorders. Some cell-surface-anchored and molecules secreted from these parasites function as virulence markers, of which peptide hydrolases, particularly cysteine proteases (CPs), are abundant and have versatile lytic activities. Upon secretion, CPs can affect host tissues and immune responses beyond the site of parasite colonization, thereby increasing the pathogens' virulence. The four intestinal protists considered here are known to secrete predominantly clan A (C1- and C2-type) CPs, some of which have been characterized. CPs of Giardia duodenalis (e.g., Giardipain-1) and Entamoeba histolytica (EhCPs 1-6 and EhCP112) degrade mucin and villin, cause damage to intercellular junction proteins, induce apoptosis in epithelial cells and degrade immunoglobulins, cytokines and defensins. In Cryptosporidium, five Cryptopains are encoded in its genome, but only Cryptopains 4 and 5 are likely secreted. In Blastocystis sp., a legumain-activated CP, called Blastopain-1, and legumain itself have been detected in the extracellular medium, and the former has similar adverse effects on epithelial integrity and enterocyte survival. Due to their different functions, these enzymes could represent novel drug targets. Indeed, some promising results with CP inhibitors, such as vinyl sulfones (K11777 and WRR605), the garlic derivative, allicin, and purified amoebic CPs have been obtained in experimental models, suggesting that these enzymes might be useful drug targets.
Insights
Intestinal parasites like Giardia and Entamoeba cause severe diarrhea. Their secreted cysteine proteases (CPs) damage host cells and immune defenses, offering potential drug targets for treating these diseases.
Area of Science:
- Parasitology
- Molecular Biology
- Immunology
Background:
- Intestinal protistan parasites (Giardia, Entamoeba, Cryptosporidium, Blastocystis) cause significant global health burdens, leading to severe diarrhea and inflammation.
- These pathogens disrupt epithelial barrier function, increase intestinal permeability, and induce enterocyte apoptosis, contributing to host physiological and immunological disorders.
- Secreted parasite molecules, particularly cysteine proteases (CPs), act as virulence factors, damaging host tissues and modulating immune responses.
Purpose of the Study:
- To investigate the role of cysteine proteases (CPs) from four major intestinal protistan parasites as potential therapeutic targets.
- To highlight the mechanisms by which CPs contribute to parasite virulence and host tissue damage.
- To review the potential of CP inhibitors in treating parasitic intestinal diseases.
Main Methods:
- Literature review and analysis of characterized cysteine proteases from Giardia, Entamoeba, Cryptosporidium, and Blastocystis.
- Examination of the known functions and substrates of secreted CPs, including their effects on host cells and immune molecules.
- Assessment of experimental data on the efficacy of CP inhibitors in preclinical models.
Main Results:
- CPs from Giardia and Entamoeba degrade key host proteins like mucin and villin, compromise intercellular junctions, induce apoptosis, and degrade immune components.
- While Cryptosporidium has multiple CPs, only Cryptopains 4 and 5 are suggested to be secreted.
- Blastocystis secretes a legumain-activated CP (Blastopain-1) that impairs epithelial integrity and enterocyte survival.
Conclusions:
- Secreted cysteine proteases are crucial virulence factors for intestinal protistan parasites, contributing to disease pathogenesis.
- The characterized functions of CPs in degrading host tissues and immune factors underscore their importance in parasitic infections.
- CPs represent promising novel drug targets, with early studies showing efficacy of inhibitors like vinyl sulfones and allicin in experimental models.
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