Manganese is Lyme disease’s double-edge sword

For decades, Lyme disease has frustrated both physicians and patients alike. Caused by the corkscrew-shaped bacterium Borrelia burgdorferi, the infection, if left untreated, can linger for months, leading to fever, fatigue and painful inflammation.

In a new study, Northwestern University and Uniformed Services University (USU) scientists have uncovered a surprising — and ironic — vulnerability in the hardy bacterium. By exploiting this vulnerability, researchers could help disarm B. burgdorferi, potentially leading to new therapeutic strategies for Lyme disease.

The Northwestern and USU team discovered that manganese, which helps shield B. burgdorferi against its host’s immune system, is simultaneously also a crack in its armor. If B. burgdorferi is either starved of or overloaded with manganese, the bacteria become highly vulnerable to the host’s immune system or treatments they would otherwise resist.

The study will be published on Thursday (Nov. 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.”

Hoffman is the Charles E. and Emma H. Morrison Professor of Chemistry and molecular biosciences at Northwestern’s Weinberg College of Arts and Sciences. He also is a member of the Chemistry of Life Processes Institute and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Daly is an emeritus professor of pathology at USU.

Since the 1980s, the occurrence of Lyme disease has increased dramatically across North America and around the globe. According to the Centers for Disease Control and Prevention, roughly 476,000 people in the United States are diagnosed annually. Currently, there are no approved vaccines against the disease, and long-term use of antibiotics is problematic. 

“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 a series of previous studies, Hoffman and Daly collaborated to understand the role of manganese in Deinococcus radiodurans, a radiation-resistant bacteria known as “Conan the Bacterium” for its extraordinary ability to survive harsh conditions. Now, they wanted to see if manganese played a role in B. burgdorferi’sdefenses.

To conduct the study, the team used a new tool called electron paramagnetic resonance (EPR) imaging to characterize the atomic composition of manganese inside the living bacteria. To add even finer detail, the team harnessed electron nuclear double resonance (ENDOR) spectroscopy to examine the atoms surrounding manganese. Together, the technologies created a molecular map, showing which forms of manganese were present, where they were located and how they changed under stress.

The “map” revealed a two-tier, manganese-based defense system comprising an enzyme called MnSOD and a pool of manganese metabolites. To withstand bombardment from the host’s immune system, the bacteria first use MnSOD, which acts like a shield. If any oxygen radicals slip past this shield, they are met with the metabolite pool, which acts like a sponge to soak up and neutralize those 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 scientists found the bacteria constantly juggle where to send the manganese — to the MnSOD enzymes or the metabolite pool. Too little manganese and the bacteria lose their defense mechanisms. But, as the microbes age, their metabolite pools dramatically shrink, leaving them exposed to damage and stress. At this point, too much manganese becomes toxic because the bacteria can no longer store it safely.

This discovery holds potential for new Lyme disease therapies. Future drugs could starve the bacterium of manganese, disrupt its ability to form protective manganese complexes or even push it into toxic overload. Any of these approaches would leave B. burgdorferi wide open to attack by the 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.”

The study, “EPR spectroscopy reveals antioxidant manganese defenses in the Lyme disease pathogen Borrelia burgdorferi,” was supported by the Congressionally Directed Medical Research Programs’ Tick-borne Disease Research Program (award number TB180110) and the National Institutes of Health (award number GM111097). Additional funds were from the Defense Threat Reduction Agency (award number HDTRA1620354) and National Institute of Allergy and Infectious Diseases (award numbers R01AI080615 and P01AI138949). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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