The AlternativeTranslational Profile That Underlies the Immune-Evasive State of Persistence in Chlamydiaceae Exploits Differential Tryptophan Contents of the Protein Repertoire

Abstract

SUMMARY One form of immune evasion is a developmental state called “persistence” whereby chlamydial pathogens respond to the host-mediated withdrawal of l -tryptophan (Trp). A sophisticated survival mode of reversible quiescence is implemented. A mechanism has evolved which suppresses gene products necessary for rapid pathogen proliferation but allows expression of gene products that underlie the morphological and developmental characteristics of persistence. This switch from one translational profile to an alternative translational profile of newly synthesized proteins is proposed to be accomplished by maximizing the Trp content of some proteins needed for rapid proliferation (e.g., ADP/ATP translocase, hexose-phosphate transporter, phosphoenolpyruvate [PEP] carboxykinase, the Trp transporter, the Pmp protein superfamily for cell adhesion and antigenic variation, and components of the cell division pathway) while minimizing the Trp content of other proteins supporting the state of persistence. The Trp starvation mechanism is best understood in the human- Chlamydia trachomatis relationship, but the similarity of up-Trp and down-Trp proteomic profiles in all of the pathogenic Chlamydiaceae suggests that Trp availability is an underlying cue relied upon by this family of pathogens to trigger developmental transitions. The biochemically expensive pathogen strategy of selectively increased Trp usage to guide the translational profile can be leveraged significantly with minimal overall Trp usage by (i) regional concentration of Trp residue placements, (ii) amplified Trp content of a single protein that is required for expression or maturation of multiple proteins with low Trp content, and (iii) Achilles'-heel vulnerabilities of complex pathways to high Trp content of one or a few enzymes.

Animal Models for Studying Female Genital Tract Infection with Chlamydia trachomatis

“…C. trachomatis has a degraded cytotoxin, mostly nonfunctional, although differences in functionality at the serovar level have been reported (66). C. muridarum has three paralogous cytotoxin copies (67) and produces functional cytotoxins. Since C. muridarum and C. trachomatis show a difference in their responses to IFN-␥ (32), a cytokine that plays an important role in the early clearance of Chlamydia from the genital tract (68), both species will probably also differ in their responses to other cytokines.…”

Evolution to a Chronic Disease Niche Correlates with Increased Sensitivity to Tryptophan Availability for the Obligate Intracellular Bacterium Chlamydia pneumoniae

“…While this provocative hypothesis seems to fit the C. trachomatis data best, it may also be partly supported by the limited C. pneumoniae data that are available. Lo et al (121) reported that MurA is a low-tryptophan-containing enzyme, making it more suited to expression during persistence. Indeed, when Timms et al (123) evaluated murA transcription in the IFN-␥ model of C. pneumoniae, they found that it was upregulated 2-fold under these conditions.…”

“…Several reviews have emerged recently (121,122) suggesting that the chlamydial genus as a whole may have evolved a mechanism that mutes or downregulates selected gene products via the tryptophan levels in these key proteins. Those proteins that are required during the acute or active growth phase (i.e., normal development of Chlamydia) have higher tryptophan content, since tryptophan availability is less of an issue in this stage of growth.…”

Control of Bacterial Virulence by the RalR Regulator of the Rabbit-Specific Enteropathogenic Escherichia coli Strain E22

“…Indeed, RalR strongly activates the transcription of two genes encoding the surface-associated proteins, RalG and Aap (Fig. 5), which contain significantly more tryptophan, 2.4 to 2.6% versus 1.5%, which is the average of the complete E. coli proteome (63). Tryptophan residues are known to help translocation of surface proteins through cell membranes and serve as anchors on the periplasmic side of the membrane (64).…”

“…In E. coli, the transcription of the trpEDCBA, mtr, and tnaAB operons is tightly controlled by endogenous levels of tryptophan via TrpR-mediated repression and/or a transcriptional termination mechanism known as attenuation (61,62). Low levels of tryptophan cause an increased expression of trpEDCBA and mtr and reduced expression of tnaAB and vice versa (61)(62)(63). Further analysis using EMSA and promoter-lacZ fusions indicated that RalR neither binds to the regulatory regions of these operons nor directly regulates their expression (data not shown).…”