Elizabeth Cooney , 2025-04-23 18:00:00
It starts with the ticks. These insects infect people with the bacteria that cause Lyme disease, microbes that are complicated to study, difficult to detect when they cause illness, and challenging to treat so they don’t linger in the human body.
Understanding that bacterium, Borrelia burgdorferi, requires basic research before creating diagnostics or vaccines, slow progress that is frustrating for people affected by the chronic fatigue and brain fog of long-term Lyme disease or the joint pain of Lyme arthritis.
“It’s just fundamentally different from basically all other disease-causing agents,” Brandon Jutras, an associate professor in microbiology-immunology in the Feinberg School of Medicine at Northwestern University, told STAT. He is the senior author of two new research papers published Wednesday in Science Translational Medicine.
In both studies, the scientists used mouse models to explore unique chemical components that persist in the roughly 15% of people who don’t recover from Lyme infections and go on to develop a syndrome similar to other infection-associated illnesses, including long Covid. One study tracked antigens among the bacterial remnants that travel to the liver, and the other study screened more than 500 approved antibiotics to find one that may be safer and more effective at a lower dose than standard-of-care doxycycline.
Together, they may offer better recognition and potentially lead to alternative treatment choices for the nearly 1,200 people in the United States who develop Lyme disease every day.
The first paper studied a mouse model of Lyme disease to trace where part of the bacteria’s cell wall travels. As the bacteria grow, they spit out peptidoglycan, a component of the cell wall that acts like a large molecular bag. These remnants can still cause infection if injected into healthy mice. When it accumulates in the liver and persists for weeks, it can be a continuous source of antigens, which the immune system sees and attacks.
In previous research, the authors discovered that people with post-infectious Lyme arthritis also had that bacterial peptidoglycan cell wall floating in the synovial fluid of their inflamed joints. And consistent with other facts about this bacteria, their peptidoglycans are chemically different, too.
“We found that the unusual chemical features of the Borrelia burgdorferi peptidoglycan is what makes it able to persist,” Jutras said. “It looks like the liver is acting as a sink for these unusual pieces of peptidoglycan.”
And back to those ticks: The scientists can’t say for certain, but they suspect a sugar carried by ticks may penetrate the cell walls shed by the bacteria in ways that trap them in the liver, keeping the immune system on high alert. Those antigens from the discarded cell walls that remain may trigger post-treatment Lyme disease, which has similarities to long Covid and other infection-associated illnesses.
The peptidoglycan fragments appeared in the mouse livers even after less severe Lyme illness, but to a lesser degree.
Amy Proal, a microbiologist who is chief scientific officer at the nonprofit PolyBio Research Foundation and scientific director of the Cohen Center for Recovery from Complex Chronic Illness at Mount Sinai, told STAT studies need to go beyond the persistent antigens in the peptidoglycan cell walls and to search for the bacteria themselves. She was not involved in Wednesday’s Science Translation Medicine studies.
“When we find persistent antigen in patients with long Covid, we interpret our findings differently than this team. I think that’s a key thing to consider,” she said. “It is helpful, I guess, to know that peptidoglycan can persist a little bit longer than we thought or something. But to be most comprehensive and fully understand what can happen in people who get Borrelia and get chronic symptoms, there’d have to be some work after this to actually look for Borrelia, including in the tissue of the patients who have symptoms after Lyme disease.”
Proal said it’s possible the antigens are being actively produced by bacteria lingering in hidden reservoirs, as is the case with the SARS-CoV-2 virus in long Covid.
In response, Jutras said purified peptidoglycan, alone, persists in mice, asserting that this work suggests that Lyme can persist without the bacteria still present, because of the peptidoglycan’s unusual features.
“Peptidoglycan can be detected in human patients after oral and/or IV antibiotics. We have previously attempted to detect bacterial DNA from B. burgdorferi in the exact same patient samples tested in manuscript and were unable to do so,” he told STAT in an email. “Now, it is possible that Borrelia is still present in these human patients, but at levels that are undetectable even by quantitative PCR. That said, virtually undetectable levels of B. burgdorferi (DNA), if present, cannot explain the considerable concentrations of peptidoglycan we have measured in these samples.”
The second paper addressed drawbacks in standard antibiotic treatment for Lyme infections. Doxycycline is the go-to medication, but it can’t be given to children under age 8. Because it is a broad-spectrum antibiotic, it harms helpful members of the human microbiome while killing the bacteria that cause Lyme disease.
The scientists used a sophisticated screening process tied to Borrelia’s properties to yield piperacillin as the best choice, a member of the penicillin family that could be used at a lower dose and with fewer off-target effects. The study’s rationale was that an approved antibiotic might already be out there, just not yet found for this purpose.
“With respect to pipericillin and the antibiotic therapy, we already know that it’s safe in humans, but what we don’t know is whether it works to treat Lyme disease in humans,” Jutras said. “The obvious next step is a human clinical trial, but those are very expensive and they require federal support.”
Piperacillin hasn’t drawn much interest from the private sector because it’s a generic antibiotic.
“I think the field is making incredible strides in all facets of treatment, diagnosis, and in prevention. It’s desperately needed, given the rapid and continual expansion and increase in the number of cases and geographically speaking, where those cases are occurring,” he said. “So further supporting the research and the field in general, I think, is paramount and something that is very much in question these days.”
STAT’s coverage of chronic health issues is supported by a grant from Bloomberg Philanthropies. Our financial supporters are not involved in any decisions about our journalism.
