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

Abstract

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 altered pathways related to extracellular matrix, growth factors, integrins, and Rho GTPases. The induced transcriptional response was consistent with endothelial to mesenchymal transition, a process involved in fetal development and vascular dysfunction. This study provides a comprehensive understanding of the molecular responses of endothelial cells to T. pallidum and identified the host pathways that might cause syphilis disease symptoms, information that could aid in syphilis vaccine design. Highlights{square} Exposure of microvascular endothelial cells to Treponema pallidum subsp. Pallidum significantly alters the endothelial cell transcriptome {square}Signaling pathways related to extracellular matrix organization, growth factors, integrins, and Rho GTPases were overrepresented for genes differentially expressed in T. pallidum-exposed endothelial cells {square}Exposure to T. pallidum induces pathways and factors consistent with endothelial to mesenchymal transition, a host process central to development that may explain the devastating effects of congenital infection {square}T. pallidum exposure induces expression of Snail, the main transcription factor associated with the process of endothelial to mesenchymal transition O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=137 SRC="FIGDIR/small/651946v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@e121beorg.highwire.dtl.DTLVardef@6e4caeorg.highwire.dtl.DTLVardef@16c3f03org.highwire.dtl.DTLVardef@19cf020_HPS_FORMAT_FIGEXP M_FIG C_FIG