New Biomarkers Could Improve Early Lyme Disease Detection

Lyme disease can be easiest to treat in its earliest stages, but current tests often miss infections during that critical window and cannot tell whether bacteria are still present or were cleared years ago. New research led by Tufts University School of Medicine suggests that a group of immune molecules called anti-lipid antibodies may address these shortcomings.

The findings, published in the American Society for Microbiology journal Infection and Immunity, could lead to improved tests that identify Lyme disease earlier, when antibiotics can best prevent more debilitating disease. They also may help clinicians better identify patients who continue to experience symptoms of infection after treatment—and potentially find new drug targets to help them.

Nearly half a million Americans are diagnosed and treated for Lyme disease each year. Caused by the bacterium Borrelia burgdorferi and spread through the bite of infected blacklegged ticks (also known as deer ticks), the disease can lead to arthritis, neurological problems, and heart complications if untreated. While most patients recover after treatment, an estimated 10% to 20% continue to experience symptoms such as fatigue, pain, or cognitive difficulties, a condition known as post-treatment Lyme disease syndrome.

Current Lyme disease tests look for antibodies produced by the immune system in response to Borrelia burgdorferi bacteria. “The problem is that these antibodies don’t have the right characteristics to be clinically useful,” said Peter Gwynne, the study’s senior author and a research assistant professor at Tufts University School of Medicine. “That’s because those antibodies can take weeks to appear and often remain detectable years after the bacteria are gone.” 

Previous work by Gwynne, who is part of Tufts University Lyme Disease Initiative, and collaborators showed that Lyme disease bacteria trigger antibodies against certain lipids, or fats, that the bacteria borrow from their human hosts. Unlike antibodies used in current Lyme disease tests, these anti-lipid antibodies appear early in infection and decline after successful treatment.

Building on those earlier findings, the researchers analyzed blood samples from 199 people diagnosed with Lyme disease, including some whose symptoms persisted for months to years after treatment. They tracked anti-lipid antibody levels over time and compared them with samples from healthy volunteers and people with conditions that can resemble post-treatment Lyme disease syndrome, including lupus, multiple sclerosis, fibromyalgia, long COVID, and chronic fatigue syndrome.

Multiple analyses identified three anti-lipid antibodies that were present at higher levels during Lyme disease infection. Two of these antibodies—anti-phosphatidic acid (αPA) and anti-phosphatidylserine (αPS)—were elevated at diagnosis, even in some patients who had not yet tested positive on standard Lyme disease tests, suggesting they could help identify infections earlier. Patients with persistent symptoms after treatment were also more likely to have elevated αPS levels months later.

According to the researchers, the data suggest that a temporary elevation in these anti-lipid antibodies may indicate a new Lyme disease infection, while persistent elevation of αPS is associated with ongoing symptoms in some patients.

The new study also showed that elevated αPS levels were common among many patients with persistent Lyme disease symptoms but largely absent in people with other autoimmune and chronic illnesses that can resemble post-treatment Lyme disease syndrome.

The researchers emphasize that the findings do not yet support a new clinical test. Larger studies are needed to determine how accurately the markers identify infection and predict long-term symptoms.  

To help answer those questions, Gwynne and co-author Linden Hu, the Paul and Elaine Chervinsky Professor of Immunology at Tufts University School of Medicine, are turning to a large multi-institution study led by Tufts that follows patients for up to 15 months after a Lyme disease diagnosis. Using samples gathered from this trial, the team plans to evaluate whether anti-lipid antibodies can reliably identify early infections and distinguish patients who go on to develop prolonged symptoms.

Although the comparison groups were relatively small for the newly published research, Gwynne said the findings suggest that a different kind of immune system dysfunction may be driving persistent symptoms in Lyme disease. “If confirmed by further studies like the clinical trial, those differences could point researchers toward new therapies for people experiencing long-lasting symptoms despite being treated for Lyme disease,” he said. 

Reference: Shrestha M, Hickman AF, Zhong Y, et al. Antiphospholipid antibodies in acute and post-treatment Lyme disease. Infect Immun. 2026:e00192-26. doi: 10.1128/iai.00192-26

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