Metabolic regulation of the carbonyl stress pathway and methylglyoxal in Lyme disease and relapsing fever spirochetes
- 1Division of Biological and Biomedical Sciences, University of Montana, Missoula, Montana, United States of America
- 2Center for Biomolecular Structure and Dynamics, University of Montana, Missoula, Montana, United States of America
- 3Laboratory of Bacteriology, Rocky Mountain Laboratories, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, United States of America
Abstract
The carbonyl stress pathway in bacteria is mediated by the enigmatic metabolite methylglyoxal and is thought to be activated in response to cellular carbohydrate and phosphate imbalance. Methylglyoxal, produced from dihydroxyacetone phosphate by methylglyoxal synthase, covalently modifies nucleophilic groups of amino acid residues, such as lysine, arginine and cysteine, to yield advanced glycation end products. In this work, we have identified several environmental signals, including glycerol and peptides, which activate carbonyl stress in the Lyme disease spirochete Borrelia (Borreliella) burgdorferi. We establish that methylglyoxal production and protein glycation is dependent on the mgsA gene (bb0364) product and show that this pathway is active in Lyme disease spirochetes, but not relapsing fever Borrelia or in B. mayonii. Furthermore, we have investigated the role of carbonyl stress in the tick-mouse model of Lyme disease and provide evidence that production of methylglyoxal and glycation of proteins is not necessarily lethal, as previously believed, at least in Lyme disease spirochetes. Finally, we show that expression of the B. burgdorferi mgsA and carbonyl stress pathway in the relapsing fever spirochete B. hermsii significantly reduces the peak level of spirochetemia during the relapse phase of murine infection. Together, our results identify a new post-translation modification system in Lyme disease spirochetes that appears to be important in governing the lifestyle of this pathogen and seems to be selected against in spirochetes that reach high numbers in the blood. Author summary: The etiological agents of Lyme disease and relapsing fever are closely related bacteria in the deeply branching spirochete phylum. In North America, Lyme disease is primarily caused by Borreliella (formerly Borrelia) burgdorferi and relapsing fever is predominantly caused by Borrelia hermsii and Borrelia turicatae. Both groups of spirochetes exist in enzootic cycles involving a tick vector and a vertebrate host; however, B. burgdorferi is transmitted slowly (>48 h) by hard ticks in the genus Ixodes and persists in the tick midgut, while B. hermsii is rapidly transmitted (within minutes) by soft ticks in the genus Ornithodoros and resides in the tick salivary glands. In this study, we identify and characterize an unusual and understudied metabolic system, the carbonyl stress pathway, which is present in Lyme disease spirochetes but absent in relapsing fever spirochetes. We found this pathway is induced by external glycerol and peptides, and is mediated by methylglyoxal synthase, which converts dihydroxyacetone phosphate to methylglyoxal. Methylglyoxal is a highly reactive electrophile that modifies proteins to form advanced glycation end products that have been implicated in proinflammatory diseases. We present evidence, both in vitro and in vivo, that methylglyoxal is not necessarily lethal and that the carbonyl stress pathway controls spirochete density in the host blood during infection.
Related
- Escherichia coli hns and methylglyoxal link gut microbial metabolism to host neuronal gene regulation in Parkinson's disease.
- Presumed Paravertebral Inflammatory Pseudotumor in Relapsing Granulomatosis With Polyangiitis: Fluorodeoxyglucose (FDG) Positron Emission Tomography/Computed Tomography (PET/CT) Findings and Complete Metabolic Response to Rituximab-Based Therapy
- Metabolic regulation of ATM-KAT8-RPA1 axis in DNA damage repair and chemoresistance
- Thyroid dysfunction in aging and cardiovascular-kidney-metabolic syndrome: metabolic regulation and clinical implications
- Interferon regulatory factor 3 beyond innate immunity: Regulation in obesity and metabolic disorders
BibTeX
@article{drecktrah2026metabolic,
title = {{Metabolic regulation of the carbonyl stress pathway and methylglyoxal in Lyme disease and relapsing fever spirochetes}},
author = {Dan Drecktrah and Laura S. Hall and Britney Cheff and Crystal Richards and Sandra J. Raffel and Michael Wulf and Ian T. Bailey and Frank Gherardini and D. Scott Samuels},
journal = {PLOS Pathogens},
year = {2026},
month = sep,
doi = {10.1371/journal.ppat.1014657},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014657},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Metabolic regulation of the carbonyl stress pathway and methylglyoxal in Lyme disease and relapsing fever spirochetes
AU - Dan Drecktrah
AU - Laura S. Hall
AU - Britney Cheff
AU - Crystal Richards
AU - Sandra J. Raffel
AU - Michael Wulf
AU - Ian T. Bailey
AU - Frank Gherardini
AU - D. Scott Samuels
PY - 2026
DA - 2026/09/29
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014657
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014657
AB - The carbonyl stress pathway in bacteria is mediated by the enigmatic metabolite methylglyoxal and is thought to be activated in response to cellular carbohydrate and phosphate imbalance. Methylglyoxal, produced from dihydroxyacetone phosphate by methylglyoxal synthase, covalently modifies nucleophilic groups of amino acid residues, such as lysine, arginine and cysteine, to yield advanced glycation end products. In this work, we have identified several environmental signals, including glycerol and peptides, which activate carbonyl stress in the Lyme disease spirochete Borrelia (Borreliella) burgdorferi. We establish that methylglyoxal production and protein glycation is dependent on the mgsA gene (bb0364) product and show that this pathway is active in Lyme disease spirochetes, but not relapsing fever Borrelia or in B. mayonii. Furthermore, we have investigated the role of carbonyl stress in the tick-mouse model of Lyme disease and provide evidence that production of methylglyoxal and glycation of proteins is not necessarily lethal, as previously believed, at least in Lyme disease spirochetes. Finally, we show that expression of the B. burgdorferi mgsA and carbonyl stress pathway in the relapsing fever spirochete B. hermsii significantly reduces the peak level of spirochetemia during the relapse phase of murine infection. Together, our results identify a new post-translation modification system in Lyme disease spirochetes that appears to be important in governing the lifestyle of this pathogen and seems to be selected against in spirochetes that reach high numbers in the blood. Author summary: The etiological agents of Lyme disease and relapsing fever are closely related bacteria in the deeply branching spirochete phylum. In North America, Lyme disease is primarily caused by Borreliella (formerly Borrelia) burgdorferi and relapsing fever is predominantly caused by Borrelia hermsii and Borrelia turicatae. Both groups of spirochetes exist in enzootic cycles involving a tick vector and a vertebrate host; however, B. burgdorferi is transmitted slowly (>48 h) by hard ticks in the genus Ixodes and persists in the tick midgut, while B. hermsii is rapidly transmitted (within minutes) by soft ticks in the genus Ornithodoros and resides in the tick salivary glands. In this study, we identify and characterize an unusual and understudied metabolic system, the carbonyl stress pathway, which is present in Lyme disease spirochetes but absent in relapsing fever spirochetes. We found this pathway is induced by external glycerol and peptides, and is mediated by methylglyoxal synthase, which converts dihydroxyacetone phosphate to methylglyoxal. Methylglyoxal is a highly reactive electrophile that modifies proteins to form advanced glycation end products that have been implicated in proinflammatory diseases. We present evidence, both in vitro and in vivo, that methylglyoxal is not necessarily lethal and that the carbonyl stress pathway controls spirochete density in the host blood during infection.
SN - 1553-7374
ER -