Cases of syphilis have skyrocketed in recent years. In 2022, 205,000 cases were diagnosed in the United States, nearly double the 2018 rate. The surge is often attributed to the shutdown of the health care system during the pandemic, which made it more difficult for people to get tested for sexually transmitted infections.
Approximately 1% to 5% of people who are infected with syphilis will develop a complication of the disease called neurosyphilis. This occurs when the bacteriuma that causes syphilis, Treponema pallidum, infects the central nervous system. Neurosyphilis can be asymptomatic, but it can also be associated with stroke, muscle weakness, cognitive changes, and vision or hearing loss.
Researchers at Yale School of Medicine set out to understand why some people with syphilis develop neurosyphilis, and if there might be long-term effects of the disease on the immune system even after successful treatment with antibiotics. The results were published in the October 2, 2024 issue of the Journal of Infectious Diseases.
“Despite the long history of this disease, there’s still much we don't know about syphilis and neurosyphilis,” said Darius Mostaghimi, a medical student at Yale and first author of the study.
The researchers partnered with scientists at the University of Washington to study blood and cerebrospinal fluid from 11 participants with syphilis without neurosyphilis and 11 with neurosyphilis. The team longitudinally analyzed DNA methylation and RNA expression changes in blood cells and in cerebrospinal fluid cells.
“We found that there were different methylation signatures in both the blood and cerebrospinal fluid in people with neurosyphilis versus uncomplicated syphilis,” Mostaghimi said.
Being able to identify these changes in the blood of people with neurosyphilis suggests that in the future a blood test alone may be sufficient to diagnose the disease and avoid a lumbar puncture, which is invasive and uncomfortable.
Some of the methylation changes also corresponded to changes in the RNA expression in cerebrospinal fluid cells, suggesting that the disease causes RNA and protein changes through epigenetic mechanisms. Some of the biological pathways, such those involving insulin receptors, were not previously known to affect neurosyphilis and suggest that progression to neurosyphilis may affect how the immune system responds to blood sugar.
The researchers also collected samples of cerebrospinal fluid from nine of the participants with neurosyphilis after they were successfully treated for the disease to see if the DNA methylation changes that they saw during the active phase of disease resolved after treatment or persisted over time. They found that even after antibiotic treatment, about 80% of the DNA methylation changes in the cerebrospinal fluid remained. Because this was done in such a small sample of people, however, larger studies are necessary to confirm the significance of the findings.
“One of our big questions in general is what are the long-term consequences of having an infection that impacts the brain,” said Shelli Farhadian, MD, PhD, assistant professor of medicine (infectious diseases). “This gave us a hint that there might be epigenetic, or molecular scars that form after infection. Whether that's clinically meaningful, we don't know yet. The next step is to actually ask whether people who recovered from neurosyphilis continue to have long-term effects and whether that might be mediated in part by these molecular scars.”
Farhadian stresses that continuing to pursue research in this area is critical.
“The numbers of people being diagnosed with syphilis are really staggering,” she said. “It’s more urgent than ever to understand this ancient but still poorly understood disease.”
Additional authors include Sameet Mehta, PhD, Jennifer Yoon, Priya Kosana, Christina M. Marra, and Michael J. Corley.
To learn more, read “Epigenetic Changes in Cerebrospinal Fluid and Blood of People with Neurosyphilis.”
Darius Mostaghimi, Sameet Mehta, Jennifer Yoon, Priya Kosana, Christina M Marra, Michael J Corley, Shelli F Farhadian, Epigenetic Changes in Cerebrospinal Fluid and Blood of People with Neurosyphilis, The Journal of Infectious Diseases, 2024; https://doi.org/10.1093/infdis/jiae476
Yale School of Medicine’s Department of Internal Medicine Section of Infectious Diseases engages in comprehensive and innovative patient care, research, and educational activities for a broad range of infectious diseases. Learn more at Infectious Diseases.