For decades, Lyme disease has presented challenges for both doctors and patients. The illness is caused by the bacterium Borrelia burgdorferi, which can result in symptoms such as fever, fatigue, and inflammation if not treated early.
A recent study led by researchers from Northwestern University and Uniformed Services University (USU) has identified a vulnerability in B. burgdorferi that could be used to develop new treatments. The research found that manganese, an antioxidant used by the bacterium to defend itself against the host’s immune system, can also become a weakness for the pathogen. If B. burgdorferi is deprived of or overloaded with manganese, it becomes more susceptible to immune attacks or treatments.
“Our work shows that manganese is a double-edged sword in Lyme disease,” said Brian Hoffman of Northwestern University, who co-led the study with Michael Daly of USU. “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.”
Hoffman holds positions at Northwestern’s Weinberg College of Arts and Sciences as well as its Chemistry of Life Processes Institute and Robert H. Lurie Comprehensive Cancer Center. Daly is an emeritus professor at USU.
Lyme disease cases have risen significantly since the 1980s across North America and globally. According to data from the Centers for Disease Control and Prevention, about 476,000 people are diagnosed each year in the United States alone. There are currently no approved vaccines for Lyme disease, and long-term antibiotic use poses additional risks because antibiotics can also harm beneficial gut bacteria.
“Although antibiotics harm B. burgdorferi, they also kill beneficial gut bacteria,” Daly said. “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.”
In earlier studies on Deinococcus radiodurans—a highly radiation-resistant bacterium—Hoffman and Daly explored how manganese contributed to bacterial defenses under extreme conditions. Their latest research applied advanced techniques like electron paramagnetic resonance (EPR) imaging and electron nuclear double resonance (ENDOR) spectroscopy to map how B. burgdorferi uses manganese within living cells.
The team discovered a two-tier defense involving an enzyme called MnSOD and a pool of manganese metabolites inside B. burgdorferi. MnSOD acts as a shield against oxidative stress from the host's immune response; any remaining threats are managed by metabolite pools that neutralize toxic molecules.
“Our study demonstrates the power of EPR and ENDOR spectroscopies for uncovering hidden biochemical mechanisms in pathogens,” Hoffman said. “Without these tools, B. burgdorferi’s defense system and weak spots would have remained invisible.”
The research revealed that B. burgdorferi must carefully balance where it allocates manganese between these protective systems: too little leaves it defenseless; too much becomes toxic when storage capacity declines with age.
This finding suggests possible new directions for therapy—drugs might either limit available manganese or disrupt its safe storage within the bacteria during infection.
“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.”
The study was published November 13 in mBio journal with support from several agencies including Congressionally Directed Medical Research Programs’ Tick-borne Disease Research Program, National Institutes of Health, Defense Threat Reduction Agency, and National Institute of Allergy and Infectious Diseases.