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

Ashok Aiyar,Shardulendra P Sherchand,David H Martin,Alison J Quayle,Robert J Belland,Theresa L Chang,Arnold H Zea,Lyndsey R Buckner

doi:10.3389/fcimb.2014.00072

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.

Highlights

Chlamydia trachomatis is an obligate intracellular bacterium that has a unique biphasic developmental cycle
The purpose of this review is to: (a) describe the recent advances made in the characterization of the normal and perturbed vaginal microbiome that are pertinent to the indole-rescue hypothesis; (b) describe recent in vivo data to support and extend this hypothesis, including evidence that C. trachomatis can adopt a persistent growth mode in vivo, and that Bacterial vaginosis (BV) provides an indole-rich genital environment; and (c) explicate the mechanism by which BV and/or the vaginal Trichomonas vaginalis (TV) co-infections could modulate the effect of IFNγ on C. trachomatis growth and clearance in vivo, including ramifications on clinical outcomes and choice of treatment
Consistent with this, IFNγ exposure induces a chlamydial pattern of gene expression that causes an up-regulation of genes that can synthesize tryptophan through indole salvage and a down-regulation of genes necessary for later stages of the chlamydial normal development cycle

Summary

Introduction

Chlamydia trachomatis is an obligate intracellular bacterium that has a unique biphasic developmental cycle. Infected, untreated women can vertically transmit their infection to neonates, with consequences including pneumonia. Despite extensive public health interventions including education, screening, and antibiotic treatment, C. trachomatis infections remain a significant global health problem, with reported U.S cases reaching 1 million in 2006 and continuing to rise since (Centers for Disease Control, 2011). This burden of cases, together with the predominantly asymptomatic nature of the disease, have led the C. trachomatis infection to be called the “silent epidemic” (Wallis, 2001). The development of a vaccine is considered a priori in the control of this infection

Objectives

Findings

Conclusion