Influence of the tryptophan-indole-IFNγ axis on human genital Chlamydia trachomatis infection: role of vaginal co-infections

Abstract

The natural history of genital Chlamydia trachomatis infections can vary widely; infections can spontaneously resolve but can also last from months to years, potentially progressing to cause significant pathology. The host and bacterial factors underlying this wide variation are not completely understood, but emphasize the bacterium's capacity to evade/adapt to the genital immune response, and/or exploit local environmental conditions to survive this immune response. IFNγ is considered to be a primary host protective cytokine against endocervical C. trachomatis infections. IFNγ acts by inducing the host enzyme indoleamine 2,3-dioxgenase, which catabolizes tryptophan, thereby depriving the bacterium of this essential amino acid. In vitro studies have revealed that tryptophan deprivation causes Chlamydia to enter a viable but non-infectious growth pattern that is termed a persistent growth form, characterized by a unique morphology and gene expression pattern. Provision of tryptophan can reactivate the bacterium to the normal developmental cycle. There is a significant difference in the capacity of ocular and genital C. trachomatis serovars to counter tryptophan deprivation. The latter uniquely encode a functional tryptophan synthase to synthesize tryptophan via indole salvage, should indole be available in the infection microenvironment. In vitro studies have confirmed the capacity of indole to mitigate the effects of IFNγ; it has been suggested that a perturbed vaginal microbiome may provide a source of indole in vivo. Consistent with this hypothesis, the microbiome associated with bacterial vaginosis includes species that encode a tryptophanase to produce indole. In this review, we discuss the natural history of genital chlamydial infections, morphological and molecular changes imposed by IFNγ on Chlamydia, and finally, the microenvironmental conditions associated with vaginal co-infections that can ameliorate the effects of IFNγ on C. trachomatis.

Keywords: Chlamydia trachomatis; IDO1; IFNγ; bacterial vaginosis; indole; persistence; tryptophan; vaginal microbiome.

Figure 1

IFNγ levels in paired endocervical secretion samples from women during, and post-antibiotic resolution, of C. trachomatis infection. Endocervical secretions, harvested as previously described (Gumbi et al., 2008), were collected from 11 women during an ongoing NAAT+ C. trachomatis infection, and again 3–6 weeks after azithromycin treatment and a confirmed NAAT− C. trachomatis test. Samples were quantified using multiplex cytokine analysis (Millipore), and comparisons between infected and non-infected states investigated by a Wilcoxon-Mann-Whitney test. A p-value of < 0.05 was considered significant. CT+ indicates samples from patients with an active infection and FU indicates post-antibiotic follow-up samples.