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.

Beyond Tryptophan Synthase: Identification of Genes That Contribute to Chlamydia trachomatis Survival during Gamma Interferon-Induced Persistence and Reactivation

“…It has been previously shown that Salmonella enterica serovar Typhimurium tryptophan synthase can produce ammonia and pyruvate from serine by a ␤-elimination reaction in the absence of indole (31). We speculate that TrpB P221S may not be able to bind indole but may still be able to produce ammonia, based on a hypothesis that Aiyar and colleagues proposed to explain the inactivation of tryptophan synthase in independent trachoma lineages (31). Future studies will determine if the mutant TrpB is associated with altered catalysis of the serine-indole condensation and ␤-elimination reactions.…”

“…This specimen produced few infectious EBs but contained a high Chlamydia genome load, suggesting that most of the genomes corresponded to persistent organisms (3). The observations described above suggest that C. trachomatis genital strains may rely on microbiome-derived indole to circumvent IDO1-mediated tryptophan depletion (31,32).…”

Chlamydia trachomatis: the Persistent Pathogen

“…A major component of the antichlamydial immune response, and the factor that has received the most research attention, is gamma interferon (IFN-␥) (27,28). C. trachomatis is unable to synthesize tryptophan and must obtain this essential amino acid from its host (29).…”

Učestalost i simptomatologija izmijenjene vaginalne flore kod žena na području opštine Foča

“…Kod žena sa bakterijskom vaginozom postoji povećan rizik za polno prenosive infekcije uzrokovane Neisseria gonorrhoeae i Chlamydia trachomatis [5], Trichomonas vaginalis [6], virusom Herpes simplex tip-2 (HSV-2) [7], virusom humane imunodeficijencije (HIV) [8], kao i različitim vrstama anaerobnih mikroorganizama koji se u povećanom broju nalaze u vaginalnom sekretu. Nedavne studije ukazuju da izmijenjena vaginalna flora kod žena sa bakterijskom vaginozom utiče na razvoj cervikalne intraepitelijalne neoplazije (CIN) [9], a udružena je i sa prevremenim porođajem i povećanim rizikom za nastanak spontanih pobačaja [10].…”