Anti-Lipid Antibodies and Cell Wall Changes Offer New Insights for Lyme Disease Diagnosis and Treatment

Two new studies are advancing the understanding of Lyme disease, offering potential improvements in early diagnosis and treatment of persistent symptoms, including Lyme arthritis.

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.

Anti-Lipid Antibodies for Earlier Diagnosis

Research led by Tufts University School of Medicine, published in the American Society for Microbiology journal Infection and Immunity, suggests that a group of immune molecules called anti-lipid antibodies may address shortcomings of current Lyme disease tests. Current tests look for antibodies produced by the immune system in response to Borrelia burgdorferi bacteria, but these antibodies can take weeks to appear and often remain detectable years after the bacteria are gone.

Previous work by the researchers 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 tests, these anti-lipid antibodies appear early in infection and decline after successful treatment.

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.

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. 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. The team is turning to a large multi-institution study led by Tufts that follows patients for up to 15 months after a Lyme disease diagnosis to evaluate whether anti-lipid antibodies can reliably identify early infections and distinguish patients who go on to develop prolonged symptoms.

Cell Wall Changes Linked to Lyme Arthritis

Separate research published in PloS Pathogens investigated how the latter phase of Lyme disease can result in musculoskeletal disease, including arthritis. The chemical structure of the Borrelia burgdorferi cell wall may dictate the frequency and severity of Lyme arthritis.

Previous research had shown that a structural component of the B. burgdorferi cell wall, peptidoglycan, is present in the joints of patients who go on to develop Lyme arthritis. The peptidoglycan present in Borrelia burgdorferi bacteria is fundamentally different from that found in other infections.

Working from the hypothesis that the composition and structure of the B. burgdorferi cell wall are essential to Lyme disease pathogenesis, researchers manipulated the peptidoglycan peptide chemical composition. They produced a bacterium that makes a modified form of peptidoglycan and found that it severely altered the ability of the organism to cause arthritis in a preclinical model of disease.

The researchers managed to mutate an enzyme involved in peptidoglycan synthesis. By deleting this gene from the bacterium's genome, they altered the chemical components of the peptidoglycan, and these changes had no effect on how the bacterium grows in culture media or if it can infect a mouse in a pre-clinical model of Lyme disease infection. However, it resulted in near total attenuation of Lyme arthritis. Even after 3 months of infection, the arthritis was virtually undetectable.

The finding further supports the role of peptidoglycan, and associated factors, in driving Lyme arthritis. Treating the inflammatory response or eliminating the inflammatory molecule may be an attractive strategy in instances in which typical therapies fail.