Squeezing the Lyme

 SMHS researchers spread the word about the prevention and possible treatment of Lyme disease.

“It’s heading west, and it’s heading north and south,” says Catherine Brissette, PhD, with not so much alarm as resignation in her voice. “With climate change, it’s exploding north into Canada, into Ontario and Manitoba. And it’s moving into places it wasn’t traditionally seen like Kentucky and Tennessee. This is a real issue.”

An associate professor in the UND Department of Biomedical Sciences since 2010, Brissette is referring to the Lyme disease spread by deer ticks in northern latitudes across the globe. The most common arthropod-borne disease affecting humans in the United States, with an estimated 300,000 cases per year, the disease bears the name of the location where it was first recognized in 1975: Lyme, Connecticut.

Having spent the better part of her career studying the corkscrew-shaped bacteria that cause Lyme, Borrelia burgdorferi, Brissette’s lab at the School of Medicine and Health Sciences is today in the middle of several research projects exploring not merely the spread of Lyme but also its pathology.

brissette
Catherine Brissette, PhD

“There are lots of different manifestations of neurological Lyme disease and most of them are treated with antibiotics and things end up fine. But there’s a portion of people who even after extensive treatment continue to have these symptoms that linger.”

“There are lots of different manifestations of neurological Lyme disease and most of them are treated with antibiotics and things end up fine,” says Brissette from her office in UND’s Neuroscience Research Facility. “But there’s a portion of people who even after extensive treatment continue to have these symptoms that linger.”

As Brissette puts it, while most persons who acquire Lyme disease from a tick bite undergo successful antibiotic treatment, up to 20 percent of patients suffer from a chronic condition that has been designated Post-Treatment Lyme Disease Syndrome (PTLDS). Symptoms of PTLDS are primarily neurological in nature and include, among other symptoms, chronic fatigue, pain, cognitive impairment, migraine headaches, balance issues, weakness, facial palsy, and vertigo.

 

“So we asked ‘why?’”

So Brissette and her team asked “Why?”—what was contributing to this syndrome so long after treatment? Although possible answers to that question abound, so far there has been little evidence to support any of them.

“The first theory is that the antibiotics simply didn’t work—and that the patient needed more. But the evidence here is weak,” Brissette continues, noting that several clinical trials exploring this question have not shown benefit for patients taking a longer course of antibiotic treatment.

However, two newer—and potentially more promising— solutions to the PTLDS puzzle have emerged that involve a complex mixture of immunology, neurology, and genetics.

The first involves the notion that the “debris” left behind by the dead bacteria following a course of antibiotics may either cross the blood-brain barrier or otherwise generate an inflammatory response from the person’s immune system, causing patients’ neurological symptoms.

“There’s some evidence for this both in animals and humans in terms of Lyme arthritis,” Brissette says, using the knee joint as an example. “There’s not a lot of vasculature there. So, if you have dead bacteria hanging out in the knee that doesn’t get cleared by the immune system because there’s not a lot of cellular traffic coming through, it stays. And then you have this stimulus where the immune system is going to keep trying to clear out these foreign bodies, but it can’t.”

Although researchers don’t yet have solid evidence that there’s any Borrelia debris in the brain specifically creating PTLDS symptoms, scientists in Brissette’s lab, including third-year SMHS medical student Jacob Greenmyer, did learn something interesting recently in this regard.

“Jacob showed that if you take some of the cells from the brain—like microglia, which are normally responsible for clearing debris and responding to injury and inflammation—and expose them to dead and living bacteria, they respond more strongly to busted up bacteria than to live bacteria,” explains

Brissette. “That suggests to us that this bacterial debris could be driving this inflammatory response. This is why we also wondered if treating people with long-term antibiotics might in some cases be making things worse.”

The other promising idea is that researchers are wondering whether even after bacteria are cleared from the body the initial insult they triggered throws off the balance of the immune systems of some patients predisposed to inflammation—at the genetic level. Like a teeter-totter, the body’s various systems need balance; a certain amount of inflammation is necessary to kill pathogens and clear them away. But too much inflammation will damage the host tissue and could result in an alteration of the expression of certain genes in a person’s DNA.

“That balance is important and if that balance is skewed you could have long-term problems, even if there’s no longer any bacteria or debris there,” Brissette says. “It’s like you’ve flipped the switch but now it can’t get turned off. And one way that can happen is through epigenetic mechanisms where you have a modification to DNA where a gene that might normally get turned off stays on because of some change to the DNA structure.”

 

Earlier diagnosis and treatment

One of several researchers working on National Institutes of Health-funded Centers of Biomedical Research Excellence (CoBRE) projects at UND, Brissette is part of a group focused on studying host-pathogen interactions. This team is busy exploring how disease-causing microbes or viruses sustain themselves within host organisms on a molecular, cellular, organismal, or population level.

“And we’ve begun to work on relapsing fever, which is spread through the bites of soft-bodied ticks,” Brissette adds. “This is a condition where fever emerges suddenly, goes away after a few days, then comes back and the pattern repeats.”

But Lyme disease, which is much more common, is still her primary focus. After all, the total direct medical costs of Lyme disease and PTLDS are estimated to be over $700 million each year in the United States alone. As such, Brissette notes that part of her mission has been getting better information into the hands of health providers to help them catch and treat the condition early.

“If you live in Minnesota and it’s August and you go to the clinic with this rash, the physician will say ‘looks like Lyme disease,’ and they’ll give you antibiotics and you’ll be likely fine,” concludes Brissette. “But if you drew that person’s blood and performed the diagnostic test for Lyme, it’d be negative.

That’s because the tests are based on the antibody responses to bacteria, and that takes time to develop. When that rash occurs within a few days of a tick bite, your body hasn’t had enough time to develop antibodies against the bacteria.”

The solution, she says, is for researchers to find a way to detect Lyme earlier, in that window of time where the characteristic bulls-eye rash—which doesn’t appear for everyone affected by Lyme—may not be present and the current blood test won’t work.

“And that’s difficult because with some diseases you have a ton of bacteria in your body and it’s easy to detect them or their products—like strep throat,” Brissette says. “But there’s not something like that with Lyme. And most of the evidence suggests that if people are treated early, they’ll show no long term problems ninety percent of the time. But the longer you go without diagnosis, the more likely it is you’re going to have chronic issues.”

By Brian James Schill