Lipid-pathogen interactions: sphingolipids in Chlamydia trachomatis infection

Survival of intracellular pathogens depends on their ability to manipulate host cells and establish a replicative niche. While protein-mediated host-pathogen interactions have been extensively studied, lipids play equally critical roles, particularly for vacuolar pathogens. By shaping the composition of the pathogen-containing vacuoles and surrounding membranes, lipid composition influences the localization of pro- and anti-pathogen factors, controls membrane fusion, regulates nutrient delivery, and affects vacuole stability. In this review, we focus on the diverse roles of sphingolipids during infection by the vacuolar obligate intracellular bacterium, Chlamydia trachomatis. We first discuss the importance of host sphingolipids, in particular sphingomyelin, and the two proposed models for its acquisition. We then highlight recent findings showing how sphingolipids contribute to infection by establishing and maintaining a permissive niche, modulating homotypic inclusion fusion, and influencing innate immune pathways. Finally, we describe how recent advances in generating trifunctional sphingomyelin derivatives have enabled visualization of sphingolipid distribution and metabolism in infected cells. Together, these findings demonstrate that sphingolipids play central roles throughout Chlamydia infection, from inclusion biogenesis to immune modulation. Building on this foundation, emerging tools that visualize sphingolipids dynamics will help uncover how these lipids shape infection and guide future work in the field.