Clinical Persistence of Chlamydia Trachomatis Sexually Transmitted Strains Involves Novel Mutations in the Functional αββα Tetramer of the Tryptophan Synthase Operon

Clinical persistence of () sexually transmitted infections (STIs) is a major public health concern. persistence is known to develop through interferon gamma (IFN-γ) induction of indoleamine 2,3-dioxygenase (IDO), which catabolizes tryptophan, an essential amino acid for replication. The organism can recover from persistence by synthesizing tryptophan from indole, a substrate for the enzyme tryptophan synthase. The majority of strains, except for reference strain B/TW-5/OT, contain an operon comprised of α and β subunits that encode TrpA and TrpB, respectively, and form a functional αββα tetramer. However, mutations in ocular strains, which are responsible for the blinding eye disease known as trachoma, abrogate tryptophan synthesis from indole. We examined serial urogenital samples from a woman who had recurrent infections over 4 years despite antibiotic treatment. The isolates from each infection episode were genome sequenced and analyzed for phenotypic, structural, and functional characteristics. All isolates contained identical mutations in and developed aberrant bodies within intracellular inclusions, visualized by transmission electron microscopy, even when supplemented with indole following IFN-γ treatment. Each isolate displayed an altered αββα structure, could not synthesize tryptophan from indole, and had significantly lower expression but higher intracellular tryptophan levels compared with those of reference strain F/IC-Cal3. Our data indicate that emergent mutations in the tryptophan operon, which were previously thought to be restricted only to ocular strains, likely resulted in persistence in the described patient and represents a novel host-pathogen adaptive strategy for survival. () is the most common sexually transmitted bacterium with more than 131 million cases occurring annually worldwide. infections are often asymptomatic, persisting for many years despite treatment. recovery from persistence occurs when indole is utilized by the organism's tryptophan synthase to synthesize tryptophan, an essential amino acid for replication. Ocular but not urogenital strains contain mutations in the synthase that abrogate tryptophan synthesis. Here, we discovered that the genomes of serial isolates from a woman with recurrent, treated STIs over many years were identical with a novel synthase mutation. This likely allowed long-term persistence where active infection resumed only when tryptophan became available. Our findings indicate an emerging adaptive host-pathogen evolutionary strategy for survival in the urogenital tract that will prompt the field to further explore chlamydial persistence, evaluate the genetics of mutant strains and fitness within the host, and their implications for disease pathogenesis.