A far-reaching study conducted by scientists at Cincinnati Children’s reports that the Epstein-Barr virus (EBV) — best known for causing mononucleosis — also increases the risks for some people of developing seven other major diseases.
Those diseases are: systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), celiac disease, and type 1 diabetes. Combined, these seven diseases affect nearly 8 million people in the U.S.
Study results published April 12 in the journal Nature Genetics. The project was led by three scientists: John Harley, MD, PhD, Director of the Center for Autoimmune Genomics and Etiology (CAGE) at Cincinnati Children’s and a faculty member of the Cincinnati VA Medical Center; Leah Kottyan, PhD, an immunobiology expert with CAGE; and Matthew Weirauch, PhD, a computational biologist with the center. Critical contributions were provided by Xiaoting Chen, PhD, and Mario Pujato, PhD, both also in CAGE.
The study shows that a protein produced by the Epstein-Barr virus, called EBNA2, binds to multiple locations along the human genome that are associated with these seven diseases.
Overall, the study sheds new light on how environmental factors, such as viral or bacterial infections, poor diet, pollution or other hazardous exposures, can interact with the human genetic blueprint and have disease-influencing consequences.
“Now, using genomic methods that were not available 10 years ago, it appears that components made by the virus interact with human DNA in the places where the genetic risk of disease is increased,” Harley says. “And not just for lupus, but all these other diseases, too.”
The full impact of this study could take years to explore. Here are some of the initial implications:
New concern about the ‘kissing disease’
EBV is a strikingly common virus. In the US and other developed nations, more than 90 percent of the population becomes infected by age 20. In less-developed nations, 90 percent of people become infected by age 2. Once infected, the virus remains in people for their entire lives.
Mononucleosis, which causes weeks of extreme fatigue, is the most common illness caused by EBV. Mono was nicknamed the “kissing disease” years ago because the virus spreads primarily via contact with saliva.
Over the years, scientists have linked EBV to a few other rare conditions, including certain cancers of the lymphatic system. Harley, who has devoted much of his career to studying lupus, found possible connections between lupus and EBV years ago. That work includes proposing mechanisms that the immune system uses in response to the virus that lead to lupus, and showing that children with lupus almost always are infected with EBV.
Today’s study adds weight to those lupus findings and adds six more well-known diseases to the list.
“This discovery is probably fundamental enough that it will spur many other scientists around the world to reconsider this virus in these disorders,” Harley says. “As a consequence, and assuming that others can replicate our findings, that could lead to therapies, ways of prevention, and ways of anticipating disease that don’t now exist.” So far, no vaccine exists that will prevent EBV infection.
“I think we’ve come up with a really strong rationale for encouraging people to come up with more of an effort,” Kottyan says. “Some EBV vaccines are under development. I think this study might well encourage them to push forward faster and with rededicated effort.”
How EBV hijacks our immune system
When viral and bacterial infections strike, our bodies respond by commanding B cells within our immune systems to crank out antibodies to battle the invaders. However, when EBV infections occur, something unusual happens.
The EBV virus invades the B cells themselves, re-programs them, and takes over control of their functions. The Cincinnati Children’s research team has discovered a new clue about how the virus does this, a process that involves tiny proteins called transcription factors.
Our bodies have about 1,600 known transcription factors at work within our genome. Each cell uses a subset of these to become what they are and to respond to their environment. These proteins constantly move along the strands of our DNA, turning specific genes on and off to make sure cells function as expected.
However, when the transcription factors change what they do, the normal functions of the cell can also change, and that can lead to disease. The Cincinnati Children’s team suspects that the EBNA2 transcription factor from EBV is helping change how infected B cells operate, and how the body responds to those infected cells.
The new paper shows that seven seemingly unrelated disease states actually share a common set of abnormal transcription factors, each affected by the EBNA2 protein from the Epstein-Barr virus. When these EBNA2-related clusters of transcription factors attach themselves to one portion of the genetic code, the risk of lupus appears to rise. When those same transcription factors land on another part of the code, the risk of multiple sclerosis appears to rise. And so on.
“Normally, we think of the transcription factors that regulate human gene expression as being human,” Kottyan says. “But in this case, when this virus infects cells, the virus makes its own transcription factors, and those sit on the human genome at lupus risk variants (and at the variants for other diseases) and that’s what we suspect is increasing risk for the disease.”
New leads emerge for improving treatment
It remains unclear how many cases of the seven diseases listed in the study can be traced to prior EBV infection. More genomic analyses involving many more patients with these diseases will be required to make reliable estimates.
“The impact of the virus is likely to vary across the diseases,” Harley says. “In lupus and MS, for example, the virus could account for a large percentage of those cases. We do not have a sense of the proportion in which the virus could be important in the other EBNA2-associated diseases.”
However, the breakthrough identification of specific transcription factors connected to EBV infections opens new lines of study that could accelerate efforts to find cures.
“This same cast of characters is a villain in multiple immune-related diseases,” Weirauch says. “They’re playing that role through different ways, and doing it at different places in your genome, but it’s the same sinister characters. So if we could develop therapies to stop them from doing this, then it would help multiple diseases.”
A number of compounds — some experimental, some approved as medications for other conditions — already are known to be capable of blocking some of the high-risk transcription factors listed in the paper, Weirauch says. Teams at Cincinnati Children’s have begun deeper studies of some of these compounds.
Findings go far, far beyond EBV
While the EBV-related findings involved more than 60 human proteins linked to seven diseases, the Cincinnati Children’s research team already has taken a huge next step. They applied the same analytic techniques to tease out connections between all 1,600 known transcription factors and the known gene variants associated with more than 200 diseases.
The results of that massive cross-analysis also appear in today’s study. Intriguing associations were documented involving 94 conditions.
“Our study has uncovered potential leads for many other diseases, including breast cancer,” Harley says. “We cannot possibly follow up on all of these, but we are hoping that other scientists will.”
After devoting decades of research to hunting down the causes of lupus, Harley says this study represents the most important discovery of his career. “I’ve been a co-author in almost 500 papers. This one is more important than all of the rest put together. It is a capstone to a career in medical research,” he says.
Software behind discoveries to be made public
Detecting and tracking the activities of these transcription factors took years of work involving dozens of laboratory and computational experts.
The project required gathering massive sets of genetic data, then analyzing every genetic change affecting the activity of the virus. Doing this required creating two new algorithms, called RELI and MARIO, which were developed at Cincinnati Children’s by Weirauch and colleagues.
Both software tools and a related website will be made publicly available.
“We are going to great lengths to not only make the computer code available, but all of the data and all of the results,” Weirauch says. “We think it’s an interesting approach that could have implications for many diseases, so we’re contacting experts on the various diseases and sharing the results and seeing if they want to collaborate to follow up on them.”
GLOSSARY OF TERMS
What is the Epstein-Barr virus?
The Epstein-Barr virus (EBV) is an extremely common virus usually spread by saliva. EBV causes mononucleosis, and has been associated with a growing number of other diseases. A study led by Cincinnati Children’s, published today in Nature Genetics, adds seven diseases to that list.
What is mononucleosis?
Also known as “mono,” and nicknamed the “kissing disease,” the symptoms of this condition include extreme fatigue, fever, sore throat, head and body aches, swollen lymph nodes in the neck and armpits, swollen liver or spleen or both, and rash, according to the Centers for Disease Control and Prevention. Most people get better in two to four weeks. However, some people may feel fatigued for several more weeks.
What is a B cell?
B cells are a type of white blood cell found in the immune system. These cells produce antibodies in reaction to infections by bacteria, viruses and other invaders. Epstein-Barr virus infects a small proportion of these cells.
What is a transcription factor?
Transcription factors are proteins that “turn on and turn off” genes. These proteins help direct cell growth, division, and death. They also control cell migration and organization. There are about 1,600 known human transcription factors that do their work along the human genome. These proteins change the expression of genes to make RNA, which in many cases results in forming other proteins that change how cells form and function.
What is a DNA variant?
The DNA genome of every person contains over 3 billion DNA bases. Most of the bases are exactly the same for every person. However, about 1 percent of the bases can be different and these create diversity between people. The variants can change the way proteins are made or change the regulatory processes that lead to protein production.
What is a genetic risk variant?
When a DNA variant is known to increase risk for a disease, it is called a genetic risk variant. Some variants increase risk for multiple diseases, and some variants are specific to a single disease.
How Do we Use MRSA Against Itself?
Antibiotic-resistant infections cause more than 30,000 deaths annually in the U.S. alone. The majority of those are caused by methicillin-resistant Staphylococcus aureus, more commonly known as MRSA, which can turn routine medical operations into near-death battles.
MRSA evolved to become a deadly killer because it’s wily and resilient. A new Michigan State University study, however, is figuring out how to turn one of its strengths against it.
“Attacking the cell membrane and inhibiting its ability to produce lipids, or fats, could be an effective treatment protocol,” said Neal Hammer, MSU assistant professor of microbiology and molecular genetics, and senior author of the study that appears in the current issue of the Journal of Bacteriology. “MRSA, though, bypasses the effects of fatty acid inhibitors by absorbing human lipids.”
Antibiotic resistance is a significant challenge in modern medicine. Pathogens encode genes to stay one step ahead, and scientists conduct research that will hopefully stop them, Hammer added.
The study began with the already established fact that MRSA has a genetic hardwired, fat-absorbing pathway. In an evolutionary arms race, MRSA’s ability to absorb human fat and use it as a shield of sorts gives it an advantage. The scientists asked what was the source of the fatty acids in humans?
The answer lay in a simple test that many of us take each year.
Human blood is filled with lipids — good and bad cholesterol — that everyone knew existed but didn’t connect to MRSA. The scientists suggest that MRSA steals these fatty acids and then integrates the lipids into its own cell membrane. This allows it to resist antimicrobials that target fatty acid synthesis. And since there’s plenty of these fatty acids in the blood and liver, MRSA has a veritable endless buffet on which to feast.
“MRSA secretes enzymes, called ‘lipases,’ that free the fatty acids in human LDLs, or bad cholesterol,” Hammer said. “We used mass spectrometry to identify how MRSA was able to perform this feat — the first time this process has been observed.”
Past research laid the groundwork for this discovery. Many of those studies focused on fatty sources found on human skin. This emphasis was due in part to knowing that as much as 30 percent of the world’s population carry MRSA on their skin — without any detrimental health effects.
Now that Hammer’s team is shining the scientific spotlight on how MRSA consumes fatty acids present in the host, future research can focus on these new targets and preventing MRSA from obtaining host fatty acids. This could be a strategy to improve the efficacy of triclosan, an antibacterial agent used in hospitals and found in many household products, as well as other bacterial fatty acid synthesis inhibitors.
The interdisciplinary team of MSU scientists who were part of the study includes: Phillip Delekta, John Shook, Todd Lydic and Martha Mulks.
Does Body Odour Point the Way to Malaria?
Typhoid Mary may have infected a hundred or more people, but asymptomatic carriers of malaria infect far more people every year. An international team of researchers is working toward a way to identify malaria patients including infected individuals who show no malaria symptoms.
People who have malaria but are not symptomatic abound in the heaviest areas of malaria infestation. Even blood tests do not necessarily pick up infection with the plasmodium parasite, especially at low parasite densities. DNA tests for the parasite usually show infection, but they are far from rapid.
“Our previous work in a mouse model found that malaria infection altered the odors of infected mice in ways that made them more attractive to mosquitoes, particularly at a stage of infection where the transmissible stage of the parasite was present at high levels,” said Consuelo De Moraes, adjunct professor of biology, Penn State, and professor of environmental systems science, ETH Zurich. “We also found long-term changes in the odor profiles of infected mice.”
The researchers wanted to see if they could identify changes in human odors associated with malaria infection that might be useful for diagnosing infected individuals. They were particularly interested in identifying those who were infected, but had no symptoms. The researchers initially used microscopy and an SD Bioline Rapid Diagnostic Test to identify patients with malaria. Because these methods have limited sensitivity, particularly when parasite loads are low, infections were confirmed by DNA tests. They identified 333 people who unambiguously were either infected with malaria or were not infected with malaria.
Only if both microscopy and DNA studies were negative were subjects considered malaria-free. Infected patients for the initial studies were both microscopy and DNA positive for malaria. In some later analyses, the researchers included 77 people who were positive for malaria according to DNA, but showed no parasites in the microscopic tests.Malaria infection does not create new volatile chemicals in the body, but alters the amounts — up or down — of volatile chemicals that are already present in the odors of healthy people.
“It is interesting that the symptomatic and asymptomatic infections were different from each other as well as from healthy people,” said Mark C. Mescher, adjunct professor of biology, Penn State, and professor of environmental systems science, ETH Zurich.
This difference among infected, infected asymptomatic, and healthy individuals may eventually lead to tests capable of rapidly and accurately identifying infected people, even those without symptoms.
The researchers report in today’s (May 14) issue of Proceedings of the National Academy of Sciences that predictive models using machine learning reliably identify infection status based on volatile biomarkers. They state “our models identified asymptomatic infections with 100 percent sensitivity, even in the case of low-level infections not detectable by microscopy.” These results far exceed any currently available rapid diagnostic tests.
“But, we should emphasize that we are a long way away from developing a practical diagnostic assay based on odor cues,” said De Moraes.
For a test to succeed it would need to be rapidly and cheaply deployable under field conditions, but still detect infections with high sensitivity.
“In the near term, our goal is to refine the current findings to find the most reliable and effective biomarkers we can,” said Mescher. “This is really basic science to identify the biomarkers of malaria. There is still a lot more work to be done to develop a practical diagnostic assay.”
The Common Cold: Could we be Close to a Cure
The appropriately named common cold strikes the average adult two to three times per year, and children even more regularly.
Currently, there is no way to prevent a common cold, and once it has arrived, there is no way to get rid of it.
Despite the impressively high-tech world we are living in, medical research cannot yet defeat this foe. All we can do is treat its symptoms and hold tight until it has passed.
Why is the common cold difficult to tackle?
The common cold has evaded medical science’s advances for two primary reasons. The first issue is that there is not just one single culprit. Colds are most often caused by a rhinoviruses — a large family of viruses with hundreds of variants. This makes vaccination an impossibility and gives our immune system a challenging task.
Secondly, these viruses evolve rapidly — so even if we could produce vaccines to cover the full spectrum of rhinoviruses, they would quickly become resistant.
Although dealing with a cold is not a huge issue for most people, there are good reasons to keep hunting for ways to fight it. One person involved in the hunt is Prof. Ed Tate, of Imperial College London in the United Kingdom. He explains the importance of battling the common cold:
“The common cold is an inconvenience for most of us, but can cause serious complications in people with conditions like asthma and [chronic obstructive pulmonary disease].”
A new approach
The scientists were initially looking for a compound that would target a protein in malaria parasites. They found two likely molecules and discovered that they were most effective when they were combined.
Using advanced techniques, they combined the two molecules and produced a new compound that blocks an enzyme found in human cells, called N-myristoyltransferase (NMT).
Viruses normally steal NMT from human cells and use it to create a protective shell around their genetic information, known as the capsid. NMT is vital for the survival of cold viruses; without it, they cannot replicate and spread.
All strains of the common cold virus use this technique, so inhibiting NMT would scupper all strains of common cold virus. In fact, it should also work against the related viruses that cause foot-and-mouth disease and polio.
Also, because the molecule targets human cells rather than the virus, resistance would not be an issue. The team’s findings were recently published in the journal Nature Chemistry.
The researchers have high hopes for the drug, which currently goes under the codename of IMP-1088.
“A drug like this could be extremely beneficial if given early in infection, and we are working on making a version that could be inhaled so that it gets to the lungs quickly.”
Prof. Ed Tate
Though other drugs that target human cells in this way have been trialed before, IMP-1088 is “more than 100 times more potent” than its predecessors.
Also, earlier drugs designed to block NMT were too toxic to be of benefit. This new drug, however, did not damage cultured human cells. Of course, more research will be needed to confirm that the drug is safe for use.
Another concern is outlined by Prof. Tate, who explains, “The way the drug works means that we would need to be sure it was being used against the cold virus, and not similar conditions with different causes, to minimize the chance of toxic side effects.”
So, we are not there yet, but we are as close as we have ever been to a cure for the common cold.
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