Dissemination of Chlamydia from the reproductive tract to the gastro-intestinal tract occurs in stages and relies on Chlamydia transport by host cells.

Chlamydia trachomatis is a Gram-negative bacterial pathogen and a major cause of sexually transmitted disease and preventable blindness. In women, infections with C. trachomatis may lead to pelvic inflammatory disease (PID), ectopic pregnancy, chronic pelvic pain, and infertility. In addition to infecting the female reproductive tract (FRT), Chlamydia spp. are routinely found in the gastro-intestinal (GI) tract of animals and humans and can be a reservoir for reinfection of the FRT. Whether Chlamydia disseminates from the FRT to the GI tract via internal routes remains unknown. Using mouse-specific C. muridarum as a model pathogen we show that Chlamydia disseminates from the FRT to the GI tract in a stepwise manner, by first infecting the FRT-draining iliac lymph nodes (ILNs), then the spleen, then the GI tract. Tissue CD11c+ DCs mediate the first step: FRT to ILN Chlamydia transport, which relies on CCR7:CCL21/CCL19 signaling. The second step, Chlamydia transport from ILN to the spleen, also relies on cell transport. However, this step is dependent on cell migration mediated by sphingosine 1-phosphate (S1P) signaling. Finally, spleen to GI tract Chlamydia spread is the third critical step, and is significantly hindered in splenectomized mice. Inhibition of Chlamydia dissemination significantly reduces or precludes the induction of Chlamydia-specific serum IgG antibodies, presence of which is correlated with FRT pathology in women. This study reveals important insights in context of Chlamydia spp. pathogenesis and will inform the development of therapeutic targets and vaccines to combat this pathogen.