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The iron-dependent repressor YtgR is a tryptophan-dependent attenuator of the trpRBA operon in Chlamydia trachomatis.

ABSTRACT: The trp operon of Chlamydia trachomatis is organized differently from other model bacteria. It contains trpR, an intergenic region (IGR), and the biosynthetic trpB and trpA open-reading frames. TrpR is a tryptophan-dependent repressor that regulates the major promoter (P_trpR), while the IGR harbors an alternative promoter (P_trpBA) and an operator sequence for the iron-dependent repressor YtgR to regulate trpBA expression. Here, we report that YtgR repression at P_trpBA is also dependent on tryptophan by regulating YtgR levels through a rare triple-tryptophan motif (WWW) in the YtgCR precursor. Inhibiting translation during tryptophan limitation at the WWW motif subsequently promotes Rho-independent transcription termination of ytgR, thereby de-repressing P_trpBA. Thus, YtgR represents an alternative strategy to attenuate trpBA expression, expanding the repertoire for trp operon attenuation beyond TrpL- and TRAP-mediated mechanisms described in other bacteria. Furthermore, repurposing the iron-dependent repressor YtgR underscores the fundamental importance of maintaining tryptophan-dependent attenuation of the trpRBA operon.

SUBMITTER: Pokorzynski ND

PROVIDER: S-EPMC7755916 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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The iron-dependent repressor YtgR is a tryptophan-dependent attenuator of the trpRBA operon in Chlamydia trachomatis.

Pokorzynski Nick D ND Hatch Nathan D ND Ouellette Scot P SP Carabeo Rey A RA

Nature communications 20201222 1

The trp operon of Chlamydia trachomatis is organized differently from other model bacteria. It contains trpR, an intergenic region (IGR), and the biosynthetic trpB and trpA open-reading frames. TrpR is a tryptophan-dependent repressor that regulates the major promoter (PtrpR), while the IGR harbors an alternative promoter (PtrpBA) and an operator sequence for the iron-dependent repressor YtgR to regulate trpBA expression. Here, we report that YtgR repression at PtrpBA< ...[more]

PMID: 33353937

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Project description:Chlamydia trachomatis and Streptococcus pyogenes are among the most prevalent bacterial pathogens of humans. Interestingly, both pathogens are tryptophan (Trp) auxotrophs and must acquire this essential amino acid from their environment. For Chlamydia, an obligate intracellular bacterium, this means scavenging Trp from the host cell in which they reside. For Streptococcus, a primarily extracellular bacterium, this means scavenging Trp from the local environment. In the course of a natural immune response, both pathogens can be exposed to Trp-limiting conditions through the action of the interferon gamma-inducible IDO1 enzyme, which catabolizes Trp to N-formylkynurenine. How these pathogens respond to Trp starvation is incompletely understood. However, we have previously demonstrated that genes enriched in Trp codons were preferentially transcribed in C. pneumoniae during Trp limitation. Chlamydia, but not Streptococcus, lacks a stringent response, which is a global regulon activated by uncharged tRNAs binding in the A site of the ribosome. We hypothesized that the chlamydial response to Trp limitation is a consequence of lacking a stringent response. To test this, we compared global transcription profiles of C. trachomatis to both wild-type and stringent response mutant strains of Streptococcus during Trp starvation. We observed that both Trp auxotrophs respond with codon-dependent changes in their transcriptional profiles that correlate with Trp codon content but not transcript stability. Importantly, the stringent response had no impact on these transcriptional changes, suggesting an evolutionarily conserved adaptation to Trp starvation. Therefore, we have revealed a novel response of Trp auxotrophic pathogens in response to Trp starvation. IMPORTANCE Chlamydia trachomatis and Streptococcus pyogenes are important pathogens of humans. Interestingly, both are auxotrophic for tryptophan and acquire this essential amino acid from the host environment. However, part of the host defense against pathogens includes the degradation of tryptophan pools. Therefore, Chlamydia and Streptococcus are particularly susceptible to tryptophan starvation. Most model bacteria respond to amino acid starvation by using a global regulon called the stringent response. However, Chlamydia lacks a stringent response. Here, we investigated the chlamydial response to tryptophan starvation and compared it to both wild-type and stringent response mutant strains of S. pyogenes to determine what role a functional stringent response plays during tryptophan starvation in these pathogens. We determined that both of these pathogens respond to tryptophan starvation by increasing transcription of tryptophan codon-rich genes. This effect was not dependent on the stringent response and highlights a previously unrecognized and potentially evolutionarily conserved mechanism for surviving tryptophan starvation.

Project description:Clinical persistence of Chlamydia trachomatis (Ct) sexually transmitted infections (STIs) is a major public health concern. In vitro 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 Ct replication. The organism can recover from persistence by synthesizing tryptophan from indole, a substrate for the enzyme tryptophan synthase. The majority of Ct 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, trpA mutations in ocular Ct 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 Ct infections over 4 years despite antibiotic treatment. The Ct isolates from each infection episode were genome sequenced and analyzed for phenotypic, structural, and functional characteristics. All isolates contained identical mutations in trpA 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 trpBA expression but higher intracellular tryptophan levels compared with those of reference Ct strain F/IC-Cal3. Our data indicate that emergent mutations in the tryptophan operon, which were previously thought to be restricted only to ocular Ct strains, likely resulted in in vivo persistence in the described patient and represents a novel host-pathogen adaptive strategy for survival.IMPORTANCEChlamydia trachomatis (Ct) is the most common sexually transmitted bacterium with more than 131 million cases occurring annually worldwide. Ct infections are often asymptomatic, persisting for many years despite treatment. In vitro 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 Ct 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 Ct STIs over many years were identical with a novel synthase mutation. This likely allowed long-term in vivo 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 Ct strains and fitness within the host, and their implications for disease pathogenesis.

Dataset Information

The iron-dependent repressor YtgR is a tryptophan-dependent attenuator of the trpRBA operon in Chlamydia trachomatis.

Publications

The iron-dependent repressor YtgR is a tryptophan-dependent attenuator of the trpRBA operon in Chlamydia trachomatis.

Similar Datasets

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