For decades, Lyme disease has frustrated physicians and patients alike. Caused by corkscrew shaped bacteria borrelia burgdorferiIf left untreated, the infection can persist for months, causing fever, fatigue, and painful swelling.
In a new study, scientists at Northwestern University and Uniformed Services Universities (USU) have revealed a surprising – and ironic – vulnerability in a hardy bacterium. By exploiting this vulnerability, researchers could help disarm B. burgdorferiPotentially leading to new therapeutic strategies for Lyme disease.
Northwestern and USU team discover manganese that helps shield B. burgdorferi Against its host’s immune system, there is a crack in its armor as well. If B. burgdorferi When either rich or starved of manganese, the bacteria become highly sensitive to the host’s immune system or treatments they would otherwise resist.
The study was published today (November 13) in the journal MBAO.
“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. “This is both Borrelia’s armor and its weakness. If we can target the way it handles manganese, we could open the door to entirely new approaches to treating Lyme disease.”
Hoffman is the Charles E. and Emma H. Morrison Professor of Chemistry and Molecular Biology in Northwestern’s Weinberg College of Arts and Sciences. He is also a member of the Chemistry of Life Processes Institute and the Robert H. Lurie Comprehensive Cancer Center at Northwestern University. Daly is Emeritus Professor of Pathology at USU.
Since the 1980s, the incidence of Lyme disease has increased dramatically throughout North America and around the world. According to the Centers for Disease Control and Prevention, approximately 476,000 people are diagnosed annually in the United States. Currently, there is no approved vaccine against this disease, and long-term use of antibiotics is problematic.
“Although antibiotics cause harm B. burgdorferiThey also kill beneficial gut bacteria,” Daly said. “Lyme disease is spread through tick bites and — if not treated promptly — can cause long-term 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 Bacteria” for its extraordinary ability to survive in harsh conditions. Now, they wanted to see if manganese played a role in B. burgdorferi’s rescue.
To conduct the study, the team used a new tool called electron paramagnetic resonance (EPR) imaging to characterize the atomic structure of manganese inside living bacteria. To add even finer detail, the team used electron atomic double resonance (ENDOR) spectroscopy to examine the atoms surrounding the 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-tiered, manganese-based defense system involving 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 through this shield, they encounter the metabolite pool, which acts like a sponge to absorb and neutralize those toxic molecules.
“Our study demonstrates the power of EPR and ENDOR spectroscopy to uncover hidden biochemical mechanisms in pathogens,” Hoffman said. “Without these tools, B. burgdorferi“The defense system and vulnerabilities will remain invisible.”
The scientists found that the bacteria are constantly searching for where to send the manganese – to the MnSOD enzymes or to the metabolite pool. Too little manganese and the bacteria lose their defense mechanisms. But, as microbes age, their metabolite pools shrink dramatically, leaving them more exposed to damage and stress. At this point, too much manganese becomes toxic because the bacteria can no longer store it safely.
This discovery has the potential for new treatments for Lyme disease. Future drugs could starve the bacterium of manganese, disrupting its ability to form protective manganese complexes or even pushing it into toxic overload. Any of these approaches will leave B. burgdorferi Open to attack by the immune system.
“By disrupting the delicate balance of manganese B. burgdorferiIt may be possible to weaken the pathogen during infection,” Daly said. “Manganese is an Achilles’ heel of its protection.”
notes
The study was supported by the Tick-Borne Disease Research Program of the Congressionally Directed Medical Research Program and the National Institutes of Health. Additional funding was from the Defense Threat Reduction Agency and the National Institute of Allergy and Infectious Diseases.