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

Abstract

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.

Chlamydia trachomatis Infection Impairs MHC-I Intracellular Trafficking and Antigen Cross-Presentation by Dendritic Cells

“…Our findings support the notion that by interfering with Rabcontrolled intracellular transport, C. trachomatis hijacks antigen cross-presentation and conspires against an efficient cytotoxic CD8+ T cell immune response, turning DCs into a convenient vehicle for bacterial spreading. In mice, C. muridarum spreads from genital tissues to the gastrointestinal tract in a staged transport involving genital tissue/ganglion, ganglion/spleen, and spleen/gastrointestinal tract (53,54). Accordingly, in humans C. trachomatis was found in the intestine regardless of sexual behavior, suggesting a putative similar spreading way (54)(55)(56).…”

Quo vadis? Central Rules of Pathogen and Disease Tropism

“…( Zhang et al., 2008 ; Zhang et al., 2014 )], or pharmacological modulation [ e.g. ( Thaiss et al., 2018 ; Howe et al., 2019 ; Bryden et al., 2020 ; Grau et al., 2020 )]. Mendelian randomization may show utility in select cases to validate host determinants in humans ( Reilly et al., 2018 ), but may only be sufficiently powered for very prevalent pathogens.…”

“…group A Streptococci, mediated by capsule hyaluronan interaction with lymphatic vessel endothelial receptor 1 ( Lynskey et al., 2015 )], infection of mobile host cells [ e.g. Chlamydia trachomatis infection of dendritic cells ( Howe et al., 2019 )] or by taking advantage of cell-cell connections [ e.g. HSV-1 dissemination from initial sites of vaginal colonization to the dorsal root ganglia, then spine, and then colon enteric nervous system via peripheral nociceptors ( Khoury-Hanold et al., 2016 )].…”

“…Colonizing additional sites is influenced by many of the same factors that influence initial colonization: nutrient and host cell availability ( McCall et al., 2015 ; Quinn et al., 2020 ; Sungnak et al., 2020 ; Ziegler et al., 2020 ), competition ( Lam and Monack, 2014 ), thermal and stress tolerance ( Scull et al., 2009 ; McCall and Matlashewski, 2010 ; McCall and Matlashewski, 2012 ), surviving immune responses, for example through colonization of immune privileged organs (see above, as for T. gondii or T. brucei ) ( Saeij et al., 2005 ; McCall and McKerrow, 2014 ) or co-opting defense pathways [ e.g. ( Mandal et al., 2017 ; Howe et al., 2019 ; Ziegler et al., 2020 )]. For the multiple pathogens that initially show broad tissue tropism followed by more restrictive tropism [ e.g.…”

Vaccines: Underlying Principles of Design and Testing

“…Chlamydia muridarium (C. muridarium) is used to model C. trachomatis in inbred mice. C. muridarium infection induces pathology in the genital tract of female mice, 56 however, in contrast to women, C. muridarium undergoes significant dissemination to other tissues, 57 inducing much stronger circulating adaptive immunity than reported to date in humans. 58 Unsurprisingly, these differences can impact the outcome of challenge experiments to test vaccine efficacy.…”