CARABEO, R. | Search bioRxiv

bioRxiv2022

Pathogen-driven induction of a host transcriptome facilitating epithelial-to-mesenchymal transition

The obligate intracellular pathogen Chlamydia trachomatis is the causative agent of the most common bacterial sexually transmitted disease worldwide. While the host response to infection by this pathogen has been well characterized, it remains unclear to what extent host gene expression during infection is the product of Chlamydia-directed modulation of host transcription factors. In this report, we show the transcriptome of Chlamydia-infected epithelial cells exhibits gene expression consistent with activity of YAP, a transcriptional coactivator implicated in cell proliferation, organ morphogenesis, wound healing, and fibrosis. After confirming induction of YAP target genes during infection, we observed increased YAP nuclear translocation in Chlamydia-infected epithelial cells. We show that increased YAP activation is a Chlamydia-directed process occurring during midcycle infection; critically, this phenotype is sensitive to inhibition of protein synthesis by the pathogen. Infection-mediated YAP activation bypasses YAP inhibition by the Hippo kinase cascade, instead involving YAP tyrosine phospho-activation and the activity of host Src family kinases. Taken together, our results define a mechanism for Chlamydia-directed modulation of host gene expression independent of the host inflammatory response to infection, as well as introduce novel therapeutic targets for treatment of this pervasive disease.

cell biology↗

bioRxiv2021

Host cell amplification of nutritional stress contributes to persistence in Chlamydia trachomatis

Persistence, a viable but non-replicating growth state, has been implicated in diseases caused by Chlamydia trachomatis. Starvation of distinct nutrients produce a superficially similar persistent state, implying convergence on a common intracellular environment. We employed host-pathogen dual RNA-sequencing under both iron- and tryptophan-starved conditions to systematically characterize the persistent chlamydial transcriptome and to define common contributions of the host cell transcriptional stress response in shaping the intracellular environment. The transcriptome of the infected host cells was highly specific to each nutritional stress, despite comparable effects on chlamydial growth and development in each condition. In contrast, the chlamydial transcriptomes between nutritional conditions were highly similar, suggesting some overlap in host cell responses to iron limitation and tryptophan starvation that contribute to a common persistent phenotype. We demonstrate that a commonality in the host cell responses is the suppression of guanosine triphosphate (GTP) biosynthesis, a nucleotide for which Chlamydia are auxotrophic. Pharmacological inhibition of host inosine monophosphate dehydrogenase (IMPDH1), which catalyzes the rate-limiting step in de novo guanine nucleotide synthesis, resulted in comparable GTP depletion to both iron and tryptophan starvation and induced chlamydial persistence. Moreover, IMPDH1 inhibition and iron starvation acted synergistically to control chlamydial growth. Thus, host cell reduction in GTP levels amplifies the nutritional stress to intracellular chlamydiae in infection-relevant models of persistence, illustrating the determinative role the infected host cell plays in bacterial stress responses. IMPORTANCEBacteria respond to nutritional stress through universal and unique mechanisms. Genome reduction in the Chlamydiaceae, a consequence of coevolution with their obligate eukaryotic hosts, has reduced their repertoire of stress response mechanisms. Here we demonstrate that the infected host cell may provide the context within which universal stress responses emerge for Chlamydia trachomatis. We report that during starvation of the essential nutrients iron or tryptophan, a common response of the infected epithelial cell is the suppression of GTP biosynthesis, which induces a persistent developmental state in the pathogen. Thus, chlamydial persistence results from the combined effects of primary stresses on the pathogen and the host, with the latter eliciting a secondary host cell response that intensifies the inhospitable intracellular environment.

microbiology↗