Date of Award

January 2025

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Shelli Farhadian

Abstract

In addition to causing acute illness, infections, even following successful treatment, can both increase risk for developing or cause new, emergent disease, including neurological and psychiatric disease. Despite this understanding, a comprehensive and overarching examination of the relationship between various neurological and psychiatric diseases with infections is missing from the scientific corpus. This thesis aims to enumerate the evidence for the relationship between various neurologic and psychiatric diseases with infection and describe proposed mechanisms for how infections affect risk for developing these diseases. We use this birds-eye framing of post-infectious neurological sequelae to better understand our case-control study on acute neurosyphilis and post-treatment neurosyphilis. Despite neurosyphilis’ long history, its pathogenesis is not well-characterized, especially with regards to how it affects individuals following antibiotic treatment. Therefore, we aim to characterize neurosyphilis (NS) pathogenesis before treatment and assess cellular changes following treatment. We longitudinally analyzed DNA methylation and RNA expression changes in cerebrospinal fluid (CSF) cells and peripheral blood mononuclear cells (PBMCs) from 11 participants with laboratory-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-compound, and insulin-response pathways. Despite antibiotic treatment, approximately 80% of CSF methylation changes persisted; suggesting that epigenetic scars accompanying NS may persistently affect immunity following infection. Future studies must examine whether these sequelae are clinically meaningful.

Comments

This thesis is restricted to Yale network users only. It will be made publicly available on 05/14/2027

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