Researchers investigate the underlying causes of post-treatment Lyme disease syndrome

If someone is bitten by a tick and develops Lyme disease, they may have flu-like symptoms, including fatigue, fever, headaches, muscle and joint aches, and swollen lymph nodes. If caught early, a two-to-four-week course of the antibiotic doxycycline is usually an effective treatment. 

But for 10% to 30% of people who contract Lyme disease, which is caused by the bacteria Borrelia burgdorferi, their symptoms do not resolve with standard antibiotic treatment, and their condition becomes a chronic one called post-treatment Lyme disease syndrome (PTLDS).

PTLDS can cause:

• Disabling fatigue that sleep cannot fix.
• Brain fog, where finding simple words or focusing on a screen or a book becomes a monumental task.
• Widespread and persistent pain in the joints and muscles that lasts for months or even years.
• Nerve problems, ranging from twitching to numbness, tinging in the hands and feet, and even sleep disturbances.

With an estimated one million Americans afflicted with PTLDS, newly funded research at Tufts University School of Medicine seeks to determine whether the condition is triggered by a persistent autoimmune response, and if a test can be devised to pinpoint who is more likely to develop it.

The Tufts Lyme Disease Initiative is also expanding its collaborations with researchers who do not traditionally study Lyme to see if their expertise may yield new approaches to understanding what causes PTLDS. 

Current and future treatments 

Long-term treatment with antibiotics has not proven to be effective in subduing PTLDS. 

Instead, clinicians focus on treating the symptoms. Non-steroidal anti-inflammatory drugs such as ibuprofen can help with pain, and gabapentin or pregabalin may be prescribed to help treat nerve pain, specifically. Anti-depressants can help with sleep problems and mood disorders. Gentle, low-impact exercise, mindfulness-based stress reduction techniques, and getting adequate rest are also frequently recommended non-medication treatments to ease symptoms.

The symptoms of PTLDS resemble other chronic inflammatory and autoimmune diseases like lupus. In lupus, the body’s disease-fighting immune system malfunctions, mistakenly attacking its own healthy cells. 

In contrast, Lyme disease is an infection, and the immune system rightly triggers a response to fight off the bacteria. But does the human immune system fail to shut off once its work battling Lyme disease is done? Research by Peter Gwynne, research assistant professor in the Department of Molecular Biology and Microbiology at the School of Medicine, investigates that question.

“We hypothesize that chronic Lyme disease follows the same pattern: antibodies generated to fight Borrelia burgdorferi also bind to human tissues and proteins, driving the persistent inflammation that causes the symptoms that define the condition,” says Gwynne. 

Antibody proteins

In new research, funded by the Ellison Foundation, Gwynne and colleagues will look at the antibody proteins found in a small number of individuals in three different groups of patients: healthy patients, patients who had Lyme disease that was successfully treated, and people with chronic Lyme disease.

Working with CDI Labs, blood samples from those individuals will be screened against more than 20,000 known human proteins, seeking to identify antibody proteins not found in healthy patients but unique to those with resolved Lyme disease and those with chronic Lyme disease. 

“Once we identify the most promising antibodies, we will then do more in-depth research in-house to see if any antibodies common to the two Lyme groups are, perhaps, highly elevated in the those with PTLDS. We can do this using samples from hundreds of patients who are in Tufts Lyme Disease longitudinal clinical trials,” says Gwynne. 

Two-step approach

The process is a two-step approach: a discovery phase with CDI Labs to identify good targets, followed by an experimental phase in-house to validate these candidates as diagnostic markers.

Identifying disease-specific autoantibodies would close a critical gap in eradicating chronic Lyme disease, which is the absence of a definitive diagnostic test. Currently diagnosing PTLDS is more of a “diagnosis of exclusion,” Gwynne says. Doctors must rule out other causes, such as fibromyalgia, chronic fatigue syndrome, or other diseases, before confirming PTLDS. 

“If we had such a test, that would help us identify who has chronic Lyme disease and enable us to uncover, potentially, new treatments specifically aimed at it.” 

Currently, a blood test can detect the presence of antibodies to Borrelia burgdorferi, but since the body can produce those antibodies for years after an active infection is gone, the test is not a definite diagnosis of a new infection.

The brain factor

Chris Dulla, the Annetta and Gustav Grisard Chair and Professor of Neuroscience at the School of Medicine, does not study Lyme disease. However, he’s working with Linden Hu, the Paul and Elaine Chervinsky Professor of Immunology at the School of Medicine and co-director of Tufts Lyme Disease Initiative, to help Lyme researchers consider a related potential path to better understanding the underlying cause of the “brain fog” found in PTLDS. 

Dulla is an expert in communication among nerves and neuronal networks in the body. Disruption in the basic features of neurotransmission is associated with many neurological diseases. 

Dulla says he and Hu are discussing the hypothesis that people who develop brain fog and nerve pain from PTLDS may be suffering from the same or slightly different mechanism by which their own antibodies attack nerve cells, disrupting nerve communication.

In diseases like epilepsy and MS, this autoimmune process may permanently destroy nervous system tissue, Dulla says. In conditions like PTLDS or long COVID, the effect may still be autoimmune in nature, but more diffuse, causing signaling in the nerves to malfunction resulting in brain fog, hypersensitive to pain, or numbness. 

“Antibodies may directly interact with some brain tissue or neuronal tissue to disrupt their function, or create an immune response that attacks those tissues, resulting in some of the nerve problems and brain-fog seen in PTLDS,” Dulla suggests. 

Next steps

In 2024, Tufts received a $20.7 million grant from the National Institutes of Health to fund one of the largest and most comprehensive studies ever conducted on the causes of persistent symptoms in Lyme disease patients. The study, led by Hu, aims to enroll 1,000 participants over five years and will collaborate with multiple institutions. 

Other Tufts researchers leading this study are John Leong, the Edith Rieva and Hyman S. Trilling Professor in Geriatric Medicine and chair of the Department of Molecular Biology and Microbiology at the School of Medicine, and Sam Telford III, professor in the Department of Infectious Disease and Global Health at Cummings School of Veterinary Medicine at Tufts University. 

“That’s part of what is so promising about studying Lyme disease at Tufts,” says Hu. “We have so many researchers with cross-cutting expertise outside the Lyme disease field that we can bring in to exchange ideas. And we are collaborating with other institutions to attack Lyme disease using the best ideas from across the field. For patients with PTLDS, that means if an idea seems promising, the intellectual resources are in place to pursue it.”