Syphilis in pregnancy: placental histopathology and transcriptomic linkage to outcomes

Syphilis, caused by the spirochete Treponema pallidum subsp. pallidum (T. pallidum), is an important cause of stillbirth, preterm delivery, and neonatal death. In untreated syphilis in pregnancy, histopathologic findings of necrotizing funisitis, proliferative vascular changes in the villi, acute or chronic villitis with a predominance of CD8 T cells, and increased villous macrophages of fetal origin (Hofbauer cells) are described. Little is known about transcriptional dysregulation of immune cells in the dynamic immune microenvironment of the placental interface along a spectrum of clinical syphilis disease and treatment. The objective of this proposal is to address knowledge gaps by elucidating T pallidum-driven changes in the maternal-placental-fetal immune transcriptome, linking maternal syphilis stage, treatment timing, treponemal burden, placental histopathology, and neonatal outcomes. The central hypothesis is that adverse neonatal outcomes from syphilis, such as preterm birth, correlate with placental pathology, high treponemal burden, and transcriptional dysregulation of CD8+ T cell and Hofbauer cell populations in the placenta. In Aim 1, placental histopathologic phenotypes will be defined and correlated with treponemal burden and neonatal outcomes along a spectrum of clinical disease and compared to healthy controls. In Aim 2, differential placental gene transcriptional profiles will be linked to histopathologic placental abnormalities, preterm delivery, and congenital syphilis. As Medical Director of Perinatal Infectious Diseases at a maternity center with an annual delivery volume of over 12,000, Dr. Adhikari oversees the clinical evaluation and management of approximately 150 patients with syphilis in pregnancy every year and has collected robust preliminary clinical data. With the full support of UT Southwestern Medical Center, the Clinical and Translational Science Award Program, the Department of Obstetrics and Gynecology, and the Green Center for Reproductive Biology Sciences, as well as local and national mentors and expert advisors, Dr. Adhikari has a rich environment in which to engage in individualized mentorship and career development, formal coursework and hands-on learning to succeed. Research and training will be completed under the guidance of a robust mentorship team, including experts in placental biology, infectious diseases in pregnancy, and genomics. This K23 award will provide the training and resources needed for Dr. Adhikari to launch a successful career as an independent investigator to better define the maternal-placental-fetal immune response to infection at the cellular and molecular level and link these findings to adverse pregnancy outcomes such as preterm birth and congenital infection. Project Number: 1K23HD114892-01A1 | Fiscal Year: 2025 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Emily Adhikari | Institution: UT SOUTHWESTERN MEDICAL CENTER, DALLAS, TX | Award Amount: $167,353 | Activity Code: K23 | Study Section: Obstetrics and Maternal-Fetal Biology Study Section[CHHD-B] View on NIH RePORTER: https://reporter.nih.gov/project-details/1K23HD11489201A1