Monday, May 19, 2025
5/19/2025
Unraveling the mechanisms of cell-mediated Chlamydia systemic dissemination. - PROJECT SUMMARY/ABSTRACT Recently WHO estimated that more than 1 million new STIs are acquired daily. In 2016 of about 376 million new STIs, 127 million were caused by Chlamydia. In the US, Chlamydia continues to be a leading cause of STIs, with 1.7 million cases of approximately 2.3 million STIs reported in 2017. Chlamydial infections in women may result in cervicitis, salpingitis, pelvic inflammatory disease, causing infertility or life-threatening ectopic pregnancy. Moreover, chlamydial STIs in women are associated with increased transmission of HIV and an increased risk of cervical cancer when co-infected with HPV. In spite of great efforts, the development of mucosal vaccines that target Chlamydia has been unsuccessful. In the mouse model of infection, Chlamydia spreads from the female reproductive tract (FRT) to infect and persist in the gastro-intestinal tract (GIT). GIT infections with Chlamydia also occur in humans. In mice, following FRT infection Chlamydia muridarum (Cm) disseminates systemically in stages, by first infecting the FRT-draining iliac lymph nodes (ILNs), then the spleen, and the GIT. Cm dissemination relies on carriage by migrating host cells. Inhibition of cell migration in CCR7-/- mice or in mice treated with FTY720 diminishes or abrogates Cm spread to the spleen and the GIT. Moreover, removal of the spleen drastically reduces Cm infection of the GIT. Most importantly, removal of the spleen hinders Cm ascension in the upper FRT and abrogates the FRT pathology. We hypothesize that the spleen is a permissive site for Cm proliferation and that circulating infected cells contribute to Cm spread to the upper FRT. Therefore, the knowledge gained from the proposed work will improve our understanding of FRT immunobiology, cell migration, Chlamydia pathogenesis, and will be important for the development of vaccines and therapies to target this pathogen.
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