Treponema pallidum induces pro-inflammatory cytokine secretion in macrophages and macrophage-endothelial co-cultures

Sean WaughAkash RanasingheLisa A. ReynoldsCaroline Cameron^*

• University of Victoria, Victoria, Canada

Syphilis, caused by the extracellular bacterium Treponema pallidum ssp. pallidum, is a multi-stage and systemic infection that is lifelong in the absence of treatment. Two host cell types that frequently encounter T. pallidum during infection are endothelial cells and macrophages; treponemes disseminate through the vasculature and cross the blood–brain and placental barriers by traversing endothelial cell barriers, and macrophages are known to be critical for clearance of T. pallidum. Despite the importance of macrophages in treponemal clearance and endothelial cells in treponemal dissemination, a comprehensive understanding of the cytokines secreted by T. pallidum-exposed macrophages in the presence and absence of endothelial cells has not yet been achieved. To address this knowledge gap, we conducted time-course cytokine secretion profiling of macrophage-differentiated THP-1 cells alone and in co-culture with human brain microvascular endothelial cells. These experiments revealed reduced IL-8 secretion and increased secretion of RANTES, soluble ICAM-1, IL-1β, MCP-1, GM-CSF, TNF, and IL-6 in T. pallidum-exposed macrophage monocultures and macrophage-endothelial cell co-cultures compared to the same culture conditions in the absence of T. pallidum. These investigations enhance our understanding of macrophage-mediated, T. pallidum-focused innate immune responses occurring at endothelial sites. Further, this study provides insight into pro-inflammatory mechanisms elicited after exposure to this pathogen that may contribute to endothelial junction disruption, T. pallidum dissemination, and syphilis symptoms.