Nav: Home

Scientists create immunity to deadly parasite by manipulating host's genes

September 16, 2015

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. Exciting new research 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 via severe diarrhea worldwide each year. "This amoeba is a cluster bomb - a voracious killer," said Chelsea Marie, PhD, of the University of Virginia School of Medicine, 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."

Silence Falls

The 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 Dan Theodorescu, MD, PhD, formerly of UVA 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."

Identifying the Genes Responsible

Using next-generation sequencing, Marie identified the genes that conferred resistance and found that many were involved in managing the flow of potassium into and out of human cells. A follow-up experiment showed that E. histolytica caused intestinal cells to pump out potassium - directly before cell death. "We started to see a pretty clear line of reasoning," Theodorescu said. "The parasite was causing potassium efflux right before cell death and cells that happened to be unable to transport potassium didn't die."

"There is a clear need for new drugs targeting E. histolytica," said Marie's mentor, William A. Petri Jr., MD, PhD, chief of UVA's Division of Infectious Diseases and International Health. "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's no plan B. This could be the plan B - targeting the human genes that enable the parasite to cause disease."

The Future

Marie is pushing forward, working to make the technique used in the study more efficient and move it toward use in humans. But just demonstrating it can work is a huge accomplishment. "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 said.

The findings have been published online by the journal Scientific Reports in an article written by Marie, Hans P. Verkerke, Theodorescu and Petri.
-end-


University of Virginia Health System

Related Cancer Articles:

Radiotherapy for invasive breast cancer increases the risk of second primary lung cancer
East Asian female breast cancer patients receiving radiotherapy have a higher risk of developing second primary lung cancer.
Cancer genomics continued: Triple negative breast cancer and cancer immunotherapy
Continuing PLOS Medicine's special issue on cancer genomics, Christos Hatzis of Yale University, New Haven, Conn., USA and colleagues describe a new subtype of triple negative breast cancer that may be more amenable to treatment than other cases of this difficult-to-treat disease.
Metabolite that promotes cancer cell transformation and colorectal cancer spread identified
Osaka University researchers revealed that the metabolite D-2-hydroxyglurate (D-2HG) promotes epithelial-mesenchymal transition of colorectal cancer cells, leading them to develop features of lower adherence to neighboring cells, increased invasiveness, and greater likelihood of metastatic spread.
UH Cancer Center researcher finds new driver of an aggressive form of brain cancer
University of Hawai'i Cancer Center researchers have identified an essential driver of tumor cell invasion in glioblastoma, the most aggressive form of brain cancer that can occur at any age.
UH Cancer Center researchers develop algorithm to find precise cancer treatments
University of Hawai'i Cancer Center researchers developed a computational algorithm to analyze 'Big Data' obtained from tumor samples to better understand and treat cancer.
New analytical technology to quantify anti-cancer drugs inside cancer cells
University of Oklahoma researchers will apply a new analytical technology that could ultimately provide a powerful tool for improved treatment of cancer patients in Oklahoma and beyond.
Radiotherapy for lung cancer patients is linked to increased risk of non-cancer deaths
Researchers have found that treating patients who have early stage non-small cell lung cancer with a type of radiotherapy called stereotactic body radiation therapy is associated with a small but increased risk of death from causes other than cancer.
Cancer expert says public health and prevention measures are key to defeating cancer
Is investment in research to develop new treatments the best approach to controlling cancer?
UI Cancer Center, Governors State to address cancer disparities in south suburbs
The University of Illinois Cancer Center and Governors State University have received a joint four-year, $1.5 million grant from the National Cancer Institute to help both institutions conduct community-based research to reduce cancer-related health disparities in Chicago's south suburbs.
Leading cancer research organizations to host international cancer immunotherapy conference
The Cancer Research Institute, the Association for Cancer Immunotherapy, the European Academy of Tumor Immunology, and the American Association for Cancer Research will join forces to sponsor the first International Cancer Immunotherapy Conference at the Sheraton New York Times Square Hotel in New York, Sept.

Related Cancer Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Climate Crisis
There's no greater threat to humanity than climate change. What can we do to stop the worst consequences? This hour, TED speakers explore how we can save our planet and whether we can do it in time. Guests include climate activist Greta Thunberg, chemical engineer Jennifer Wilcox, research scientist Sean Davis, food innovator Bruce Friedrich, and psychologist Per Espen Stoknes.
Now Playing: Science for the People

#527 Honey I CRISPR'd the Kids
This week we're coming to you from Awesome Con in Washington, D.C. There, host Bethany Brookshire led a panel of three amazing guests to talk about the promise and perils of CRISPR, and what happens now that CRISPR babies have (maybe?) been born. Featuring science writer Tina Saey, molecular biologist Anne Simon, and bioethicist Alan Regenberg. A Nobel Prize winner argues banning CRISPR babies won’t work Geneticists push for a 5-year global ban on gene-edited babies A CRISPR spin-off causes unintended typos in DNA News of the first gene-edited babies ignited a firestorm The researcher who created CRISPR twins defends...