Entamoeba hystolytica Manipulates Host Ion Transport Proteins to Cause Cell Death

histolytica. They reported in the September 8, 2015, online edition of the journal Scientific Reports that they had used RNAi technology to create a library of bladder cancer cells with a multitude of independent, silenced genes. Populations of these cells were exposed to the parasite, and surviving cells were re-cultured and then exposed to the parasite again. After nine generations, cells were showing resistance to destruction by E. histolytica.

The genes of these resistant cells were analyzed with next-generation sequencing technology, which identified 281 candidate susceptibility genes. Bioinformatics analyses revealed that ion transporters were significantly enriched among these susceptibility genes, and that potassium (K+) channels were the most common transporter identified. Their importance was further supported by colon biopsy of humans with amebiasis that demonstrated suppressed K+ channel expression.

Inhibition of human K+ channels by genetic silencing, pharmacologic inhibitors, and with excess K+ protected diverse cell types from E. histolytica-induced death. Thus, it was apparent that contact with E. histolytica parasites triggered K+ channel activation and K+ efflux by intestinal epithelial cells, which preceded cell killing. Specific inhibition of Ca2+-dependent K+ channels was highly effective in preventing amebic cytotoxicity in intestinal epithelial cells and macrophages.

"There is a clear need for new drugs targeting E. histolytica," said senior author Dr. William A. Petri Jr., professor of internal medicine and pathology at the University of Virginia. "Right now there is a single antibiotic that works against this parasite. We know that eventually the parasite will develop resistance to the antibiotic and at that point there is no plan B. This could be the plan B - targeting the human genes that enable the parasite to cause disease."

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