Scientists uncover why Lyme disease symptoms may linger after treatment

Symptoms that persist long after Lyme disease is treated are not uncommon – a 2022 study found that 14% of patients who were diagnosed and treated early with antibiotic therapy would still develop Post Treatment Lyme Disease (PTLD). Yet doctors puzzle over the condition's causes and how to help their patients through symptoms ranging from severe fatigue and cognitive challenges to body pain and arthritis.

Now, Northwestern University scientists believe they know what causes the treated infection to mimic chronic illness: the body may be responding to remnants of the Borrelia burgdorferi (the bacteria that causes Lyme) cell wall, which breaks down during treatment yet lingers in the liver. This matches one theory behind the underlying causes of long COVID-19 in that persisting viral molecules may encourage a strong, albeit unnecessary, immune response, said bacteriologist Brandon L. Jutras.

"Lyme and long COVID-19 are clearly vastly different diseases, but it's possible that they share a more general mechanism of inappropriate inflammation caused by remnants of a previous infection," said Jutras, who led the research. "The maladaptive response is a product of an infection, but perhaps not necessarily an active one in all cases."

Peptidoglycan is a structural feature of virtually all bacterial cells and a common target of antibiotics, including penicillin. The research, to be published April 23 in the journal Science Translational Medicine, tracked the biodistribution of peptidoglycan from different bacteria, in real time, and found that all cell wall material is rapidly shed, but Lyme disease's peptidoglycan persists for weeks to months.

Lyme arthritis is one of the more common long-term impacts of exposure to Lyme. If a patient has a swollen knee, for instance, it is full of synovial fluid, a natural lubricant found in joints. Jutras said his team looked at the fluid in humans and found that pieces of the peptidoglycan were omnipresent weeks to months after treatment.

In the context of Lyme arthritis, if you give patients anti-inflammatory, disease-modifying antirheumatic drugs, they get better. Some of these very same patients do not get better after oral and IV antibiotics, which implies there is something unique about how patients respond at a genetic level."

Brandon L. Jutras, bacteriologist

Jutras, who joined Northwestern faculty last summer, is an associate professor of microbiology-immunology at Northwestern University Feinberg School of Medicine and a member of the Center for Human Immunobiology at Northwestern. He has been studying Lyme disease for more than 15 years, beginning in graduate school, and was previously an associate professor at Virginia Tech University.

"Peptidoglycan is kind of like a structural skeleton in virtually all bacteria, acting as a big protective bag for the bacterium," Jutras said. "Penicillin and amoxicillin and dozens of other drugs target peptidoglycan synthesis because it's a molecule that is specific to bacteria, it has similar structural features across the kingdom, and it's essential."

Lyme's peptidoglycan, however, is structurally unique, and this difference may be behind its persistence in humans. Instead of looking the same as with other bacteria, the Lyme peptidoglycan is fundamentally distinct, which is facilitated in part by sucking up sugars from its tick vector. Upon bacterial cell death – by antibiotics or the immune system – surviving molecules tend to relocate to the liver, which can't process the modified peptidoglycan.

Without this modification, it seems likely that the peptidoglycan would clear right away, as in other infections.

"The unusual chemical properties of Borrelia peptidoglycan promote persistence, but it's the individual patient response to the molecule that likely impacts the overall clinical outcome," Jutras said. "Some patients will have a more robust or stronger immune response, which could result in a worse disease outcome, while the immune system of others may largely ignore the molecule. So, in essence, it's not about whether the molecule is there or not, it's more about how an individual responds to it."

Jutras hopes the groundbreaking findings will lead to development of more accurate tests, possibly for PTLD patients, and refined treatment options when antibiotics have failed. To effectively stymie PTLD, instead of neutralizing an infection that may no longer exist, efforts are underway to neutralize the inflammatory molecule, including weaponizing monoclonal antibodies to target peptidoglycan for destruction.

The research was supported by the National Institutes of Allergy and Infectious Diseases (R21AI159800, R01AI173256, R01AI178711), the Steven & Alexandra Cohen Foundation, the Department of Defense (TB220039), the Global Lyme Alliance and the Bay Area Lyme Foundation.