Identification of the Treponema pallidum subsp. pallidum TP0092 (RpoE) Regulon and Its Implications for Pathogen Persistence in the Host and Syphilis Pathogenesis

Abstract

Bacteria often respond to harmful environmental stimuli with the induction of extracytoplasmic function (ECF) sigma () factors that in turn direct RNA polymerase to transcribe specific groups of response genes (or regulons) to minimize cellular damage and favor adaptation to the changed extracellular milieu. In Treponema pallidum subsp. pallidum, the agent of syphilis, the TP0092 gene is predicted to code for the pathogen's only annotated ECF factor, homologous to RpoE, known in Escherichia coli to control a key transduction pathway for maintenance of envelope homeostasis in response to external stress and cell growth. Here we have shown that TP0092 is highly transcribed during experimental syphilis. Furthermore, TP0092 transcription levels significantly increase as infection progresses toward immune clearance of the pathogen, suggesting a role for TP0092 in helping T. pallidum respond to harmful stimuli in the host environment. To investigate this hypothesis, we determined the TP0092 regulon at two different time points during infection using chromatin immunoprecipitation followed by high-throughput sequencing. A total of 22 chromosomal regions, all containing putative TP0092-binding sites and corresponding to as many T. pallidum genes, were identified. Noteworthy among them are the genes encoding desulfoferrodoxin and thioredoxin, involved in detoxification of reactive oxygen species (ROS). Because T. pallidum does not possess other enzymes for ROS detoxification, such as superoxide dismutase, catalase, or glutathione peroxidase, our results suggest that the TP0092 regulon is important in protecting the syphilis spirochete from damage caused by ROS produced at the site of infection during the inflammatory response.

Transcription of TP0126, Treponema pallidum Putative OmpW Homolog, Is Regulated by the Length of a Homopolymeric Guanosine Repeat

“…Recombinant T. pallidum 70 (encoded by the TP0493 gene) was expressed as a soluble recombinant protein in E. coli using the same protocol for expression and purification previously used for another T. pallidum factor ( 24 , encoded by the TP0092 gene) and the T. pallidum cyclic AMP receptor protein (CRP) homolog, encoded by TP0262 (38,39). The TP0493 gene was amplified from strain Nichols DNA as described above for the TP0126 gene.…”

The RpoE Stress Response Pathway Mediates Reduction of the Virulence of Enteropathogenic Escherichia coli by Zinc

“…RpoE is a conserved sigma factor in a variety of Gram-negative bacteria that live in complex environments (35)(36)(37). Thus, because all intestinal pathogens must be able to counteract the effects of membrane stress, it is not surprising that an RpoE-dependent envelope stress response is required for virulence in many bacteria (16)(17)(18)(19).…”

“…pallidum during an experimental syphilis infection. The authors identified 22 genes in the regulon, all with putative RpoE-binding sites (18). The alternate sigma factor RpoE is also important for Yersinia pseudotuberculosis survival in response to a number of environmental stresses, including temperature, pH, and high osmolarity (19).…”

“In Silico Metabolic Pathway Analysis and Docking Analysis of Treponema Pallidum Subs. Pallidum Nichols for Potential Drug Targets”

“…Pallidum nichols [1]. This motile, gramnegative spirochaete, can be transmitted both sexually and from mother to child and can invade virtually any organ or structure in the human body [2,3]. It rapidly disseminates from a site of inoculation in the genital region to diverse organs where it can establish persistent, even lifelong infection [4,5].…”