Original Source: http://www.dddmag.com/news/2015/09/scientists-create-immunity-deadly-parasite-manipulating-hosts-genes
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.”
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, left unimpeded, 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, Dr. William A. Petri Jr., chief of U.Va.’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.”
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.
People who become contract Naegleria fowleri may survive a little longer, or altogether, if doctors prevent their immune systems from responding to the infection. Centers for Disease Control and Prevention
Naegleria fowleri lives up to its nickname: the brain-eating amoeba. After a rush of contaminated fresh water, usually from lakes, rivers, and hot springs, enters the nose, the parasite moves up the nasal cavity toward the brain, where it feeds on cells and releases proteins that destroy brain tissue. This infection, called primary amebic meningoencephalitis (PAM), is almost always untreatable — in the U.S., only three of the 133 people who became infected since the parasite’s discovery in 1962 have survived. New approaches to treatment, however, may soon change that.
Doctors have treated the infection with the breast cancer drug miltefosine since at least 2013, when several cases of the infection emerged in Southern states. However, the parasite infects the brain so quickly — patients can die within five days of infection — that the drug is often not administered fast enough. Because of this, researchers have been looking for new treatment approaches, and a new study may have found one, suggesting that it’s the body’s own immune response that contributes to the parasite’s lethality.
Abdul Mannan Baig, of the Department of Biological and Biomedical Sciences at Aga Khan University in Pakistan, found that the brain reacts swiftly and intensely to the parasitic infection. As the parasite releases enzymes and toxins into the brain, destroying cells, the immune system mounts a counterattack, triggering an inflammatory response. This response backfires, however, causing pressure to build up and eventually break the blood-brain barrier. Thus, neuronal damage ensues not only from the ameba but also from inflammation.
Baig came to these conclusions after testing N. fowleri against brain cells in lab dishes. Brain cells paired with immune cells died about eight hours sooner than brain cells that didn’t get help from immune cells, New Scientist reported. Because of this, Baig suggested one of the first things doctors treat infected patients with is immunosuppressive drugs, and then drugs that combat PAM.
This approach could be especially beneficial to people living in Pakistan and the surrounding region, where Baig says about 20 people die each year from PAM. In the U.S., that number is far smaller. “It is worth testing, but it is very hard to test because the infection is so rare,” Jennifer Cope, of the Centers for Disease Control and Prevention, told New Scientist. Still, as climate change causes increases in temperatures across the U.S., infections may become more common.
Source: Baig AM. Pathogenesis of amoebic encephalitis: Are the amoebas being credited to an ‘inside job’ done by the host immune response? Acta Tropica. 2015.
An aedes aegypti mosquito, which spreads dengue (and chikungunya) virus. The 2014 National Climate Assessment warned that climate change is “increasing the risk of … health threats that are currently uncommon in the United States, such as dengue fever.”
CREDIT: AP PHOTO/USDA, FILE
It’s a myth there are no big winners from climate change besides fossil fuel companies.
According to one study, global warming is doubling bark beetle mating, triggering up to 60 times as many beetles attacking trees every year. The decline in creatures with shells thanks to ocean acidification “could trigger an explosion in jellyfish populations.” And climate change has helped dengue fever, which spread to 28 U.S. states back in 2009.
Of course, invasive plants will become “even more dominant in the landscape.” And who doesn’t love ratsnakes?
Let’s also not forget brain-eating parasites, which are expected to thrive as U.S. lakes heat up. That parasite — the amoeba, Naegleria fowleri — feasts on human brains like a tiny zombie. As one Centers for Disease Control and Prevention expert warned several years ago: “This is a heat-loving amoeba. As water temperatures go up, it does better. In future decades, as temperatures rise, we’d expect to see more cases.”
But this is just a taste of things to come, as two parasite experts explain in a recent article, “Evolution in action: climate change, biodiversity dynamics and emerging infectious disease [EID].” That article is part of a special April issue of the Philosophical Transactions of the Royal Society B., whose theme is “Climate change and vector-borne diseases of humans.”
“The appearance of infectious diseases in new places and new hosts, such as West Nile virus and Ebola, is a predictable result of climate change,” as the news release explains. The article examines our “current EID crisis.”
Coauthor Daniel R. Brooks explains: “It’s not that there’s going to be one ‘Andromeda Strain’ that will wipe everybody out on the planet,” he said, referring to the deadly fictional pathogen. But he warns: “There are going to be a lot of localized outbreaks that put a lot of pressure on our medical and veterinary health systems. There won’t be enough money to keep up with all of it. It will be the death of a thousand cuts.”
Many tropical diseases are tropical because their insect or animal host prefer warmer climates. A 2015 report on neglected tropical diseases by the World Health Organization (WHO) pointed out that “climate variability and long-term climate changes in temperature, rainfall and relative humidity are expected to increase the distribution and incidence of at least a subset of these diseases.” For instance, WHO notes, “dengue has already re-emerged in countries in which it had been absent for the greater part of the last century.”
The Congressionally-mandated 2014 National Climate Assessment concurs: “Large-scale changes in the environment due to climate change and extreme weather events are increasing the risk of the emergence or reemergence of health threats that are currently uncommon in the United States, such as dengue fever.”
“Some of the neglected tropical diseases are no longer strictly tropical,” said Dr. Dirk Engels, the director WHO’s Department of Control of Neglected Tropical Diseases, in a statement.
Certainly there have been major advances in the fight against many tropical diseases, but those are primarily due to medical advances and investments in public health. Such investments remain a top priority in a warming world. But the kind of extreme climate change humanity faces on our current path of unrestricted carbon pollution makes the job harder for all those focused on public health around the world.