The role of integrins and human IDO in the immune response to Chlamydia trachomatis

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The role of integrins and human IDO in the immune response to Chlamydia trachomatis

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Title: The role of integrins and human IDO in the immune response to Chlamydia trachomatis
Author: Davila, Sergio J.
Citation: Davila, Sergio J. 2016. The role of integrins and human IDO in the immune response to Chlamydia trachomatis. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
Access Status: This work is under embargo until 2018-11-01
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Abstract: Chlamydia trachomatis is the most common sexually transmitted bacterial infection in the United States. Genital C. trachomatis infections cause serious morbidity, including pelvic inflammatory disease and infertility. Multiple arms of the immune response are activated during genital C. trachomatis infection, yet this pathogen survives in its preferred human host. The lack of a vaccine and natural immunity to C. trachomatis in humans necessitate a better understanding of why the immune response fails to clear the infection.

Immune protection from C. trachomatis is dependent on interferon-γ (IFN-γ) derived from CD4+ Th1 cells. Prior to our study, the integrin receptor required for CD4+ Th1 cell trafficking to the uterus during C. trachomatis infection had not been identified. We found that C. trachomatis infection resulted in the recruitment of C. trachomatis-specific CD4+ T cells expressing the integrin α4β1. Genetic ablation or antibody blockade of α4β1, but not α4β7, function led to defective CD4+ T cell trafficking to the uterus and high bacterial load. These data show that integrin α4β1 is necessary for CD4+ T cell-mediated protection against C. trachomatis infection in the genital mucosa.

IFN-γ induces cell-autonomous antimicrobial responses, such as the expression of indoleamine 2,3-dioxygenase (IDO) in human cells. IDO converts tryptophan to kynurenine, which has been shown in human cell culture to restrict C. trachomatis, a tryptophan auxotroph. The in vivo function of IDO on C. trachomatis pathogenesis has been less characterized because IDO is not strongly expressed in mice following Chlamydia infections or IFN-γ stimulation. The absence of an animal that modeled the human cell-autonomous response prompted us to generate a transgenic mouse with tamoxifen-inducible human IDO (hIDO) expression. We found that hIDO-expressing cells from these transgenic mice restricted C. trachomatis growth in a tryptophan-dependent manner and suppressed CD4+ Th1 cells. In vivo, we observed that uterine hIDO expression initially limited C. trachomatis growth but ultimately exacerbated bacterial burden. These findings demonstrate the hIDO expression in this model is not sufficient to clear genital C. trachomatis infection. Our results imply that humans lack natural immunity to genital C. trachomatis because the pathogen evades the IDO response that is generated by IFN-γ.
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