For most victims of Lyme disease, successful treatment occurs after a two- to four-week course of antibiotics. However, for up to 20 percent of patients, the fatigue, pain, and neurocognitive difficulties persist as Post-Treatment Lyme Disease Syndrome (PTLDS).
Lyme disease is caused by a spiral-shaped bacterium known as Borrelia burgdorferi, which is the cause of more than 90 percent of all tick-borne diseases affecting humans in the United States. Estimates from the Centers for Disease Control and Prevention (CDC) suggest that Lyme disease affects 300,000 people each year. Lyme disease is a debilitating and significant public health problem that can result in arthritis, heart problems, and neurological impairment and disability.
The total direct medical costs of Lyme disease and PTLDS are estimated at over $700 million each year in the United States alone, thereby imposing a huge economic burden on healthcare. The mechanism behind PTLDS is unclear. Clinical trials suggest no long-lasting benefit of extended antibiotic treatment, and whether patients still harbor viable Borrelia burgdorferi (Bb) is unknown.
However, biomedical scientists at the University of North Dakota School of Medicine and Health Sciences are taking an innovative approach through the discipline known as epigenetics that may explain how PTLDS occurs and may lead to new treatments.
Epigenetics, meaning above the gene, is the study of how certain molecules in the cell environment surrounding the DNA that composes genes affect how those genes are expressed when the cell’s machinery for reading DNA is either free to access the cell’s DNA or inhibited. This can alter the sequences of DNA that are read, resulting in different gene expressions even though the underlying DNA sequence is unchanged.
This is analogous to a pianist who either has full access to the keys on a piano or who has to play with some of the keys taped down and not available to play each note of the melody, or in the case of cells, the bases of the genetic code. The result is a different melody or individual—even among twins—depending on the epigenetics of the individual.
Unlike the fixed genetic code, the epigenetics of individuals is subject to influences from the environment and can change over an individual’s lifetime. These changes may even be passed to offspring. Even though epigenetic changes in an individual can be inherited, the changes in gene expression are reversible.
UND’s principal investigator is Catherine A. Brissette, PhD, an assistant professor in the Department of Biomedical Sciences at the UND School of Medicine and Health Sciences. She has received a $108,000 grant from the Global Lyme Alliance, which funds research for Lyme and tick-borne disease research. She serves on the alliance’s advisory board, which serves to peer review grants in a manner similar to the National Institutes of Health. Archana Dhasarathy, PhD, and John Watt, PhD, in the SMHS Department of Biomedical Sciences are collaborating with Brissette in the research.
“Our preliminary data suggest that Bb induces substantial changes in epigenetic factors in human astrocytes,” said Brissette. “Astrocytes are critical components of the blood-brain barrier; these cells are key responders following a central nervous system injury or an infection like Lyme disease.”
The blood-brain barrier is a semipermeable membrane that protects the brain from foreign substances by allowing only some materials to enter the brain from the bloodstream. However, the barrier can be breached by infectious agents like the Bb bacterium.
“We hypothesized that neurological symptoms from Lyme disease are perpetuated by Bb-induced epigenetic changes that lead to persistent neuroinflammation,” Brissette said.
Neuroinflammation is damaging inflammation of nervous tissue from a traumatic brain injury, an infection such as Lyme disease, and other “insults” or injuries.
In their studies of neuroborreliosis, the disorder of the central nervous system caused by Bb infection, Brissette, her SMHS colleague Thad Rosenberger, and other biomedical scientists have shown that Bb-induced neuroinflammation can be reversed by supplementing the diet of their animal model with acetate. In the brain, acetate is converted to a substance that is a widely active precursor in numerous biological processes and as a substrate for a process that leads to changes in gene expression.
“Interventional oral consumption of acetate reduces the activation of astrocytes through an epigenetic modification, thus reducing inflammation,” Brissette said. “This suggests the possibility of a therapeutic.”
“Basically, can we reverse inflammation-induced changes in gene expression in the brain through a safe, oral treatment? That’s the work we would pursue in our laboratory model after we establish what are the epigenetic changes, and the extent of those changes, induced by Borrelia in our in vitro tissue culture model.”
However, Brissette cautions that epigenetic reprogramming of cells in the CNS in response to Bb could affect the fine balance between clearing the infection and causing long-term neuropathology.
“Identifying key epigenetic modifications will pinpoint novel targets for Lyme disease therapy,” she said. “Our studies will speed concrete, translational, and easily applicable treatments for neuroborreliosis and PTLDS, as well as other conditions where persistent inflammation is a concern.”
“I am excited to continue my collaboration with Dr. Dhasarathy, Dr. Watt and the very supportive epigenetics group here at the UND School of Medicine and Health Sciences Center of Biomedical Research Excellence in the Epigenomics of Development and Disease,” Brissette said.
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