Polymorphisms in Chlamydia trachomatis tryptophan synthase genes differentiate between genital and ocular isolates

Abstract

We previously reported that laboratory reference strains of Chlamydia trachomatis differing in infection organotropism correlated with inactivating mutations in the pathogen’s tryptophan synthase (trpBA) genes. Here, we have applied functional genomics to extend this work and find that the paradigm established for reference serovars also applies to clinical isolates — specifically, all ocular trachoma isolates tested have inactivating mutations in the synthase, whereas all genital isolates encode a functional enzyme. Moreover, functional enzyme activity was directly correlated to IFN-γ resistance through an indole rescue mechanism. Hence, a strong selective pressure exists for genital strains to maintain a functional synthase capable of using indole for tryptophan biosynthesis. The fact that ocular serovars (serovar B) isolated from the genital tract were found to possess a functional synthase provided further persuasive evidence of this association. These results argue that there is an important host-parasite relationship between chlamydial genital strains and the human host that determines organotropism of infection and the pathophysiology of disease. We speculate that this relationship involves the production of indole by components of the vaginal microbial flora, allowing chlamydiae to escape IFN-γ–mediated eradication and thus establish persistent infection

Chlamydia trachomatis Genital Tract Infections: When Host Immune Response and the Microbiome Collide

“…The ocular strains (serovars A-C) are characterized by localized infection of the epithelial surface of the conjunctiva. Serovars D-K are responsible for infections in the urogenital tract, especially in the endocervix [25]. Chlamydia has a unique biphasic developmental cycle which alternates between two distinct morphological forms, the elementary bodies (EBs) and the reticulate bodies (RBs) [26].…”

“…IFN-g also activates the expression of indoleamine 2,3-dioxygenase (IDO). IDO is an enzyme which catabolizes the amino acid L-tryptophan into kynurenine ( Figure 2B), depleting the host cell's pool of tryptophan [25,[56][57][58][59]. IFN-g is well known as an anti-chlamydial agent, causing inhibition of growth and development of the Chlamydia, primarily because C. trachomatis is a tryptophan auxotroph [25,[58][59][60].…”

Tryptophan synthase: a mine for enzymologists

“…TS is over-expressed in Phytophthora infestants during biotrophic and necrotrophic infection phases [88]. Moreover, inhibition of TS expressed in Chlamydia trachomatis might be useful to counteract ocular and genital infections [89,90], and inhibition of TS expressed in Mycobacterium tuberculosis and in the parasite Cryptosporidium might be a therapeutic strategy for treating tuberculosis and cryptosporidiosis, respectively [91]. The design of TS inhibitors has been pursued via both in silico methods [28,92,93] and X-ray crystallography [30].…”

Recent advances in reactive arthritis

“…In vitro, there is a dose-dependent effect of IFN-γ on C. trachomatis growth and differentiation. IFN-γ at low concentrations could inhibit chlamydial growth leading to a chlamydial "persistent state" through the induction of the tryptophandecyclizing enzyme indoleamine 2, 3-dioxygenase [26]. Depletion of the intracellular pools of tryptophan by this enzyme renders Chlamydia incapable of differentiating into infectious elementary bodies [23••].…”