Dr. Linden Hu, Vice Dean for Research at Tufts University in Boston Massachusetts and Paul and Elaine Chervinsky Professor in Immunology, discusses new and ongoing research pertaining to the prevention, treatment and diagnosis of human Lyme disease. He also discusses some of the key unanswered questions about Lyme, such as how B. burgdorferi adapts to different hosts and environments and why some patients have been known to exhibit persistent symptoms even after treatment.
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Ashley's Biggest Takeaways
- Managing Lyme disease is very important both from a public health and economic standpoint.
- Lyme disease has been growing in both numbers and geographic distribution over the last 20 years or so.
- The most recent estimate from CDC is that it affects upwards of 475 K people per year, and the cost to the U.S. economy alone is estimated to be $1-3 billion a year.
- Prevention strategies that go into the wild and try to eliminate problem at its root are challenging due to the many wild reservoirs of Borrelia burgdorferi. Fortunately, strategies targeting the main reservoirs of are likely to be effective, but they may take longer.
- Vaccines, modelled off of the work done with the rabies vaccine, which engineered the vaccinia virus to express different proteins to be used as a viral vector, were incredibly effective in the lab, however, regulatory concerns have limited the use of this vaccine in the wild.
- Doxycycline, is very effective at clearing mice, as well as ticks, from infection of B. burgdorferi and Anaplasma in the wild, however, concerns about the development of antimicrobial resistance have limited large-scale administration of the antibiotic in the wild.
- It is difficult to control the dosage of an antibiotic that is going to be administered in the wild, because you can’t control how much the mice are going to eat. Because of this, the safety profile must be high.
- Hygromycin A seems to be very well-tolerated and very safe in the laboratory—at various dosages. Doses up to 50x higher than the dose that needed to kill the bacteria did not appear to cause any harm to the animal.
- B. burgdorferi has a very small genome of about a megabase in size, much of which resides on plasmids. As a result, many things that other bacteria do for themselves, Borrelia can’t (e.g., it doesn’t produce nucleic acids or fatty acids), and it is dependent on its environment for many functions.
- Tick and mammal hosts are different in many ways. For example, ticks feed once every 6 months to a year, and they live at ambient temperature. That means that the bacteria must survive long periods of starvation, intense cold and intense heat. In a mammal host, the temperature remains the same most of the time, and there is plenty of food around. However, there is a much more sophisticated immune system trying to wipe out the invading bacteria.
- Amazingly Borrelia is able to adapt and survive in both of these environments for long periods of time. This adaptability is an area of great interest in Hu’s lab.
Featured Quotes:“As I got more into the field, I found that it was really interesting because the bacteria is very unique in lots of ways. It moves from different hosts in different environments so easily and survives in hosts so long, that there were lots of interesting things to study.”
Lyme Vaccine Research
“Back 30 years ago, when I was doing my fellowship, I was involved in human Lyme disease vaccine research. The vaccine itself was a very interesting one that created antibodies that killed the bacteria inside the tick as the tick was feeding.”
“This went forward as a human vaccine that eventually got removed from the market, due to low sales, but as we were thinking about it in our lab, we were like, ‘actually some of the characteristics of this vaccine make it much more interesting as an animal vaccine than it was as a human vaccine,’ and that’s because in the animals, if you vaccinate them, you can not only prevent the animals from getting infected, but you can also clear the ticks.”
“One of the first things we tried was a strategy for creating a vaccine for animals in the wild. And we targeted the main reservoir, which is paramyxo mice, and created a vaccine based on the human vaccine, which utilizes a protein called outer surface protein A (OspA).”
“In the laboratory, it was very effective. We were able to show that with a single dose of this vaccine, given orally, we were able to prevent 100% transmission to mice, and also clear a large percentage, I think 80-85% of the ticks from infection.”
“I think we’ve all developed a real respect for nature and how little we understand it and some of the potential implications of what we do in disturbing nature.”
“There are a couple of companies that are progressing vaccines again. Pfizer is in the middle of their Phase 3 trial of a human vaccine that’s fairly similar to the original vaccine, so there’s great hope that that will be effective. And then there are a couple of other companies advancing different strategies and platforms for human Lyme vaccines.”
Hygromycin A Shows Promise Against Lyme Disease
“One of the things we started thinking about was whether we could find a different drug, either one that wasn’t used to treat human diseases or was very narrowly targeted to the Lyme disease bacteria to replace doxycycline in these trials.”
“We were able to identify some good candidates. We work with a researcher, Kim Lewis at Northeastern University, and he’s an expert at antibiotic discovery [who] looked for antibiotics that had very narrow spectrum and were only active against Borrelia, so that we could lessen the chance of developing resistance.”
“He came up with quite a few good candidates. The one that we’re progressing right now is one called Hygromycin A, and that antibiotic was discovered years ago and abandoned because it had too narrow of a spectrum, but we found that’s its very active against spirochetes, which is the class of bacteria that B. burgdorferi is a part of. It’s also active against syphilis, but it’s not really very active against other important human pathogens like other gram-positive or gram-negative organisms.”
“We’ve been able to find doses that can clear the animal of an infection after a single dose, as well as lower doses that can clear the animals after 5-6 doses.”
What Can Be Learned About Lyme Disease from Prevention and Treatment Methods in Dogs?
“There are a couple of vaccines that are available for dogs. The other thing that’s interesting is that there are these medications that are available for dogs that you can give them and prevent tickbites and prevent transmission of tickborne disease that are not available for humans, but I think are about to be studied for use in humans, as well. So there may be some hope coming down the pipeline, and our lab is working with several of these companies to try to develop these products.”
“These medications prevent the ticks from feeding. The tick do need to attach, usually, and once they start to feed, the medication will interrupt that feeding. For Lyme disease, it takes about 48 hours for the bacteria, which reside in the tick midgut, to start replicating, after the tick has started to feed and then make it back to the salivary glands where it can make its way into the next host. So if you have a drug that can prevent feeding and get the ticks to either die or fall off before that 48 hours, you can prevent a lot of Lyme disease.”
How Borrelia burgdorferi Promotes Immune Tolerance and Why Some People Might Have Symptoms that Linger Even After Treatment
“Most people think that it’s some combination of the genetics of the specific bacteria that someone gets infected with and their own host genetics. And I think the animals might be the path for understanding where that might happen.”
“My lab does a lot of immunology, and we’re really interested in the fact that the natural hosts, for reasons that I think you can predict, don’t develop any symptoms. Because if they did develop some of the symptoms that humans get—the myocarditis or the arthritis, they would be selected against in nature. So they’ve coevolved, so this organism essentially behaves as an invasive commensal.”
“Borrelia is inside the tissues and still gets ignored, kind of the way that the gut microbiome sort of gets ignored by the immune system, so that you’re not constantly getting that inflammation."
“We’ve been looking at the mechanisms for how that might happen. One thing that happens is that something called tolerance builds over time. As you become repeatedly exposed to something, and it proves not to be dangerous to you, you start to ignore it. You have mechanisms for shutting down your immune system, so that it’s not constantly flaring up and causing problems.”
“If you knock out genes in animals that are involved in the innate immune pathway, you would have predicted that you’d get less inflammation, but what we actually see in many cases where you knock out components of the innate immune system is that you get increased inflammation.”
“Not all of that is explained by inability to control the infection. For many of these infections, they control the infection just fine, but they still get increased inflammation. And so, we think that they’re involved in this shut-down tolerance mechanism. One of our collaborators, Klemen Strle, at Wadsworth, has data suggesting that people who have an inactivating mutation, a single-nucleotide polymorphism, in one of these pathways, called Toll-like receptor I (TIL), you get increased chance for developing arthritis long-term.”
Links for This EpisodeVector-borne diseases, most of which are preventable, account for more than 17% of all infectious diseases and result in the loss of an estimated 700,000 lives annually around the world. Learn about this evolving threat and how to harness scienct to address it.
- The Bulls-Eye Rash of Lyme Disease: https://asm.org/Articles/2018/April/going-skin-deep-investigating-the-cutaneous-host-p
- Pfizer and Valneva Initiate Phase 3 Study of Lyme Disease Vaccine Candidate VLA15 https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-valneva-initiate-phase-3-study-lyme-disease
- Could This Treatment Prevent Chronic Lyme Disease? https://news.northeastern.edu/2021/10/06/preventing-chronic-lyme-disease/
- Promising New Drug Would Eradicate Lyme While Leaving Gut Microbes Alone: https://www.lymedisease.org/members/lyme-times/2022-spring-news/targeted-lyme-disease-drug/
- A Tick’s Meal: https://asm.org/Podcasts/TWiM/Episodes/A-Tick-s-Meal-TWiM-258
- Evidence That the Variable Regions of the Central Domain of VlsE Are Antigenic during Infection with Lyme Disease Spirochetes https://journals.asm.org/doi/10.1128/IAI.70.8.4196-4203.2002
- Distinct Roles for MyD88 and Toll-Like Receptors 2, 5, and 9 in Phagocytosis of Borrelia burgdorferi and Cytokine Induction https://journals.asm.org/doi/10.1128/IAI.01600-07
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