Cell Immunity Created In Parasite Responsible For 50 Million Infections

Researchers are adjusting the landscape of the human body to remove the mechanism that allows pathogens that result in disease in order to create cell immunity from the parasite E. histolytica, which has infected 50 million people and causes 40,000 to 110,000 deaths via severe diarrhea worldwide.

"It was pure luck that I ended up on this paper," Dan Theodorescu, M.D., Ph.D., director of the University of Colorado Cancer Center, said in a news release. "Bill Petri and I had been social friends for years - Christmas parties, that kind of thing. When I was at Virginia it happened that we were on a recruitment committee together and the candidate was late, so we started talking."

A conversation with William A. Petri, Jr., M.D., Ph.D., chief of the Division of Infectious Diseases & International Health at the University of Virginia led to the idea of applying an innovative cancer science technique to the study on infectious disease. After speaking with first author Chelsea Maria, Ph.D., postdoctoral researcher in the Petri Laboratory at Virginia, the group decided to silence genes in human cells to discover if the loss of any single gene would confer immunity to the parasite.

They used a technique known as RNAi to create a library of bladder cancer cells with thousands of independent, silenced genes and then challenged cultures with the parasite E. histolytica. In this case the analogue of chemotherapy was the infectious, dangerous pathogen.

During a genome-wide screen, the researchers found that E. histolytica deciminated many thousands of the independent culture cells. However, a small number of cells also seemed to resist the parasite, according to researchers. To find out if this was simply by random chance of lucky survival, they discovered the killed cells and retested the cells that survived, infecting them with E. histolytica.

"It wasn't a fluke," added Marie. "We did this over nine generations of cells, each time selecting the cells that survived and then re-applying the parasite. Over these generations of selection, we saw the cultures becoming more and more enriched for cells lacking specific genes."

They identified the genes that were resistance, largely involving the management of potassium flow into and out of human cells. They involved the following genes: KCNA3, KCNB2, KCNIP4, KCNJ3, and SLC24A3. Furthermore, a follow-up experiment showed that new intestinal cells treated with E. histolytica showed potassium efflux - the flow of potassium from inside a cell out through the cell wall - directly before cell death.

However, to ensure that lack of potassium transport was responsible for parasitic resistance, the researchers reversed the direction of their experiments. From there, they used new drugs that blocked their ability to transport potassium. And this also created cells that were resistant to E. histolytica.

"This is a major finding with translational implications for this infection that causes so many deaths worldwide, but also proof that this cancer-science approach can be used to explore genetic mechanisms of resistance in the field of infectious disease," Theodorescu concluded.

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