For decades, Lyme disease has frustrated physicians and patients alike. Caused by the bacterium Borrelia burgdorferi, the infection can lead to persistent fever, fatigue, and painful inflammation if left untreated.
In a new study, scientists from Northwestern University and Uniformed Services University (USU) have uncovered an ironic vulnerability in the hardy bacterium that could lead to new therapeutic strategies. The team discovered that manganese, a metal that shields B. burgdorferi from the host’s immune system, also serves as a critical weakness. If the bacteria are either starved of or overloaded with manganese, they become highly susceptible to immune responses and treatments they would otherwise resist.
The research was published on November 13 in the journal mBio.
“Our work shows that manganese is a double-edged sword in Lyme disease,” said Northwestern’s Brian Hoffman, who co-led the study with USU’s Michael Daly. “It’s both Borrelia’s armor and its weakness. If we can target the way it manages manganese, we could open doors for entirely new approaches for treating Lyme disease.”
Since the 1980s, the incidence of Lyme disease has increased dramatically, with the Centers for Disease Control and Prevention estimating 476,000 annual diagnoses in the United States. No approved vaccine is currently available, and long-term antibiotic use can be problematic.
“Although antibiotics harm B. burgdorferi, they also kill beneficial gut bacteria,” Daly explained. “Lyme disease is transmitted through tick bites and — if not treated promptly — can cause lingering effects by attacking the patient’s immune, circulatory and central nervous systems.”
Using advanced tools, including electron paramagnetic resonance (EPR) imaging and electron nuclear double resonance (ENDOR) spectroscopy, the team created a molecular map of manganese within the living bacteria. This revealed a two-tiered defense system: an enzyme called MnSOD acts as a primary shield against the host’s immune attack, while a pool of manganese metabolites acts as a sponge, neutralizing any toxic molecules that get past the initial defense.
The researchers found that the bacteria must constantly balance where to allocate manganese. As the microbes age, their metabolite pools shrink, leaving them exposed. At this point, an excess of manganese becomes toxic because the bacteria can no longer store it safely.
“Our study demonstrates the power of EPR and ENDOR spectroscopies for uncovering hidden biochemical mechanisms in pathogens,” Hoffman noted. “Without these tools, B. burgdorferi’s defense system and weak spots would have remained invisible.”
This discovery opens the door for future therapies that could disrupt the bacterium’s delicate manganese balance. Potential drugs could starve it of the metal, prevent it from forming protective complexes, or push it into a toxic overload, leaving it vulnerable to the body’s immune system.
“By disrupting the delicate balance of manganese in B. burgdorferi, it may be possible to weaken the pathogen during infection,” Daly said. “Manganese is an Achilles’ heel of its defenses.”
