Epigenetic Changes in Cerebrospinal Fluid and Blood of Participants with Neurosyphilis

Neurosyphilis (NS) is a complication of syphilis that affects the nervous system. Epigenetic changes within immune cells may contribute to neuroinflammation during bacterial infection, but its role in NS has not yet been established. We longitudinally analyzed DNA methylation and RNA expression changes in cerebrospinal fluid (CSF) cells and peripheral blood mononuclear cells (PBMCs) from 11 participants with lab-confirmed NS (CSF VDRL positive) and 11 matched controls with syphilis without NS (non-NS). DNA methylation profiles from CSF and PBMCs of participants with NS significantly differed from those of participants with non-NS. Some genes associated with these differentially methylated sites had corresponding RNA expression changes in the CSF (111/1097, 10.1%), which were enriched in B-cell, cytotoxic-compounds, and insulin-response pathways. Despite antibiotic treatment, approximately 80% of CSF methylation changes persisted; suggesting that epigenetic scars accompanying NS may persistently dysregulate immunity following infection. Future studies must examine whether these sequelae are clinically meaningful. Participants included in this analysis were enrolled in a study at the University of Washington which aimed to define the impact of lumbar puncture with treatment based on CSF findings on outcome of NS treatment. All participants provided written informed consent to participate. The study protocols were approved by the Research Ethics Committee of the University of Washington and Yale University. Study procedures are published . In this analysis, we strictly defined NS as a reactive CSF Venereal Disease Research Laboratory test (VDRL), and non-NS as a participant diagnosed with active syphilis with a nonreactive CSF VDRL and CSF cell count ≤5/uL . Eleven NS patients and twelve non-NS patients were recruited. CSF cells and PBMCs were collected and cryopreserved at study entry for all participants. Participants with NS were asked to return for follow-up study visits after undergoing CDC-recommended treatment for NS . Among the 11 participants with NS, 9 participants returned for lumbar puncture at week 12 post-treatment, 3 participants returned at week 24, and 4 participants returned at week 52.