For decades, Lyme disease has frustrated both physicians and patients alike. Caused by the corkscrew-shaped bacterium\u00a0Borrelia burgdorferi, the infection, if left untreated, can linger for months, leading to fever, fatigue and painful inflammation.<\/p>\n
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\u00a0B. burgdorferi, potentially leading to new therapeutic strategies for Lyme disease.<\/p>\n
The Northwestern and USU team discovered that manganese, which helps shield\u00a0B. burgdorferi\u00a0against its host’s immune system, is simultaneously also a crack in its armor. If\u00a0B. burgdorferi\u00a0is either starved of or overloaded with manganese, the bacteria become highly vulnerable to the host’s immune system or treatments they would otherwise resist.<\/p>\n
The study will be published on Thursday (Nov. 13) in the journal mBio.<\/p>\n
“Our work shows that manganese is a double-edged sword in Lyme disease,” said Northwestern’s\u00a0Brian Hoffman, who co-led the study with USU’s\u00a0Michael Daly. “It’s both\u00a0Borrelia’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.”<\/p>\n
Hoffman is the Charles E. and Emma H. Morrison Professor of Chemistry and molecular biosciences at Northwestern’s\u00a0Weinberg College of Arts and Sciences. He also is a member of the\u00a0Chemistry of Life Processes Institute\u00a0and the\u00a0Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Daly is an emeritus professor of pathology at USU.<\/p>\n
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,\u00a0roughly 476,000 people\u00a0in the United States are diagnosed annually. Currently, there are no approved vaccines against the disease, and long-term use of antibiotics is problematic.\u00a0<\/p>\n
“Although antibiotics harm\u00a0B. 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.”<\/p>\n
In a series of previous studies, Hoffman and Daly collaborated to\u00a0understand the role of manganese in\u00a0Deinococcus radiodurans,\u00a0a radiation-resistant bacteria\u00a0known as “Conan the Bacterium” for its extraordinary ability to survive harsh conditions. Now, they wanted to see if manganese played a role in\u00a0B. burgdorferi’sdefenses.<\/p>\n
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.<\/p>\n
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.<\/p>\n
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Our study demonstrates the power of EPR and ENDOR spectroscopies for uncovering hidden biochemical mechanisms in pathogens. Without these tools,\u00a0B. burgdorferi’s\u00a0defense system and weak spots would have remained invisible.”<\/p>\n
\n <\/p>\nBrian Hoffman,\u00a0the Charles E. and Emma H. Morrison Professor of Chemistry and Molecular Biosciences, Northwestern’s\u00a0Weinberg College of Arts and Sciences<\/p>\n
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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.<\/p>\n
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\u00a0B. burgdorferi\u00a0wide open to attack by the immune system.<\/p>\n
“By disrupting the delicate balance of manganese in\u00a0B. burgdorferi, it may be possible to weaken the pathogen during infection,” Daly said. “Manganese is an Achilles’ heel of its defenses.”<\/p>\n
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