There are two common approaches to protecting humans from infectious disease: targeting pathogens and parasites with medicines such as antibiotics, or dealing with the conditions that allow transmission.
Now exciting new research from the University of Virginia School of Medicine and the University of Colorado demonstrates the effectiveness of a third strategy: adjusting the landscape of the human body to remove the mechanism that allows pathogens to cause disease.
The researchers have silenced genes within human cells to induce immunity to the parasite E. histolytica, which infects 50 million people and causes 40,000 to 110,000 deaths worldwide each year via severe diarrhea. “This amoeba is a cluster bomb – a voracious killer,” said U.Va.’s Chelsea Marie, a research scientist in infectious diseases and international health, noting the challenge the researchers faced in blocking the amoeba’s ability to kill human cells. “In the back of my mind, I was thinking the parasite was going to decimate the host cells no matter what we did with their genetics.”
The research group used a technique called RNAi to create a library of bladder cancer cells with thousands of independent, silenced genes. Then they challenged these cultures with E. histolytica. “We do this all the time in cancer research,” said Dr. Dan Theodorescu, formerly of U.Va. and now director of the University of Colorado Cancer Center. “Commonly, we’re looking for genes that, when silenced, will make cells more susceptible to chemotherapy.” In this case, the analogue of chemotherapy was the infectious, dangerous pathogen.
E. histolytica proved a stubborn foe, decimating many thousands of the manipulated cell cultures. However, a small number of cells seemed to resist the parasite. Was this the random chance of lucky survival, or had silenced genes somehow provided immunity?
To find out, Marie discarded the dead cells and retested the survivors; again she infected the cells with E. histolytica. “It wasn’t a fluke,” she said. “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.”