Trends in Parasitology
ReviewTissue destruction and invasion by Entamoeba histolytica
Section snippets
Overview of amebiasis
Entamoeba histolytica is a protozoan parasite and the causative agent of amebiasis in humans. Parasite cysts are transmitted through contaminated food and water, making the incidence of disease high in areas of poor sanitation. E. histolytica is responsible for an estimated 35 to 50 million cases of symptomatic disease and approximately 100 000 deaths annually [1]. Parasite destruction of host tissue appears to be the basis of disease (Figure 1). The majority of morbidity and mortality occurs
Variable outcome of disease
E. histolytica infection occurs after the ingestion of cysts. Parasite excystation in the small intestine produces eight trophozoites per cyst, which then colonize the large intestine, existing both in the lumen and attached to mucus and epithelial cells [3]. Infection has a variable outcome, manifesting in asymptomatic colonization, diarrhea, invasive colitis, liver abscess or metastatic infection. Invasive disease pathologies, namely colitis, abscess and metastatic disease, are associated
Mechanism of host tissue destruction
E. histolytica infection has a variable outcome, but when invasive disease does occur, the potent cytotoxic activity of the parasite is likely to be a major contributor to the extensive tissue damage observed (Figure 1). The parasite is able to kill and ingest host cells in a contact-dependent manner and within minutes [24]. Other factors are likely to augment tissue destruction, such as parasite proteases and inflammatory host immune reactions. Thus, as outlined below, a combination of
Cytotoxicity
E. histolytica is cytotoxic to a variety of cell types, including neutrophils, T lymphocytes, macrophages and a variety of tissue culture lines. Although cytotoxic activity is what the parasite was named for, the precise mechanism remains an enigma. In a stepwise process, E. histolytica adheres to the target, induces its death, and then ingests the killed cell. Killing of the target cell appears to be primarily via activation of apoptosis; that is, the parasite ‘tricks’ the host cell into
What are the cytotoxic effectors?
How does E. histolytica elicit host cell death? The cumulative data demonstrate that target cell killing requires lectin-mediated contact, calcium influx, tyrosine dephosphorylation and caspase-3 activation (Figure 4). Killing is an active process because it requires parasite cytoskeletal remodeling [25] and fixed parasites do not induce sustained calcium influx [33]. There is not an isolated toxin because parasite sonicate does not induce killing [24]. These observations support a model where
Other factors contributing to tissue invasion
Because caspase inhibitors reduce liver abscess formation and caspase-3 knockout mice resist intestinal amebiasis, parasite-induced apoptosis is central to tissue destruction. However, other factors are likely to augment invasiveness, such as parasite motility, proteases and pro-inflammatory host immune reactions.
Conclusions
E. histolytica is a scourge in the developing world, with children bearing an enormous burden of developmental consequences resulting from infection. Pathogenesis appears to result from the potent cytotoxic activity of the parasite, as emphasized by the fact that inhibition of apoptosis in vivo markedly inhibits both invasive colitis and liver abscess formation. It will be of great interest to determine how the parasite effects apoptosis; namely the identities of the effectors and how they are
Acknowledgments
We thank members of our laboratory for critical reading of the manuscript. Our apologies to those whose work was not covered in this review owing to space limitations. Katherine S. Ralston is a Howard Hughes Medical Institute Fellow of the Life Sciences Research Foundation. Work in the laboratory of William A. Petri, Jr. is supported by NIH grant 5RO1 AI026649.
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