Time-course Transcriptomics Reveals Impact of Treponema pallidum on Microvascular Endothelial Cell Function and Phenotype

Syphilis, caused by Treponema pallidum subsp. pallidum, is an urgent global public health threat. Syphilis vaccine development has been impeded by limited understanding of the molecular mechanisms that enable T. pallidum to establish and maintain infection. The vascular endothelium is critical for T. pallidum attachment, dissemination, and host immune response initiation; however, the molecular details of T. pallidum-endothelial interactions are incompletely understood. To enhance understanding, we performed time-course transcriptomic profiling on T. pallidum-exposed brain microvascular endothelial cells. These analyses showed T. pallidum exposure alters pathways related to extracellular matrix, growth factors, integrins, and Rho GTPases. The induced transcriptional response was consistent with endothelial to mesenchymal transition, a key process involved in fetal development and vascular dysfunction. This study provides a comprehensive understanding of the molecular response of endothelial cells to T. pallidum and identifies the host pathways that may cause syphilis disease symptoms, information that could aid syphilis vaccine design. Overall design: This project aimed to investigate the temporal transcriptomic response of hCMEC/d3 human brain microvascular endothelial cells to T. pallidum. To complete this aim we exposed hCMEC/d3 cells to Treponema pallidum subsp. pallidum at a multiplicity of infection of 30, or a background control lacking the pathogen, and measured the endothelial transcriptional response at 45-minutes, 4-, 12-, and 24-hours post-exposure.