Polymorphisms in Chlamydia trachomatis tryptophan synthase genes differentiate between genital and ocular isolates
Harlan D. Caldwell, … , Robert J. Belland, Grant McClarty
Harlan D. Caldwell, … , Robert J. Belland, Grant McClarty
Published June 1, 2003
Citation Information: J Clin Invest. 2003;111(11):1757-1769. https://doi.org/10.1172/JCI17993.
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Article Infectious disease

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.

Authors

Harlan D. Caldwell, Heidi Wood, Debbie Crane, Robin Bailey, Robert B. Jones, David Mabey, Ian Maclean, Zeena Mohammed, Rosanna Peeling, Christine Roshick, Julius Schachter, Anthony W. Solomon, Walter E. Stamm, Robert J. Suchland, Lacey Taylor, Sheila K. West, Tom C. Quinn, Robert J. Belland, Grant McClarty

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Figure 1

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(a) Alignment of partial sequences from the trpA gene from the14 human C...
(a) Alignment of partial sequences from the trpA gene from the14 human C. trachomatis reference serovars. A ClustalW alignment of the nucleotide regions containing sequence polymorphisms is illustrated. As compared with genital serovars, ocular serovars have a three-base (nucleotides 408–410) deletion that results in the loss of a phenylalanine. The various serovars have been grouped, in accordance with their nucleotide mutational “hot-spot” sequence. The ocular serovars have a single-base deletion (nucleotide 528) resulting in a nonfunctional truncated TrpA protein. Genital serovar specific missense mutations (nucleotides 530 and 532) that result in amino acid changes in loop 6 of TrpA are shown below the nucleotide sequence. See Fehlner-Gardiner et al. (16) for details. (b) Schematic summary of the tryptophan synthase inactivating mutations identified in clinical ocular serovars and the missense mutations identified in the clinical genital serovars.