D-serine induces distinct transcriptomes in diverse Escherichia coli pathotypes

Abstract

Appropriate interpretation of environmental signals facilitates niche specificity in pathogenic bacteria. However, the responses of niche-specific pathogens to common host signals are poorly understood. D-serine (D-ser) is a toxic metabolite present in highly variable concentrations at different colonisation sites within the human host that we previously found is capable of inducing changes in gene expression. In this study, we made the striking observation that the global transcriptional response of three Escherichia coli pathotypes - enterohaemorrhagic E. coli (EHEC), uropathogenic E. coli (UPEC) and neonatal meningitis associated E. coli (NMEC) - to D-ser was highly distinct. In fact, we identified no single differentially expressed gene common to all three strains. We observed the induction of ribosome-associated genes in extraintestinal pathogens UPEC and NMEC only, and the induction of purine metabolism genes in gut-restricted EHEC and UPEC indicating distinct transcriptional responses to a common signal. UPEC and NMEC encode dsdCXA – a genetic locus required for the detoxification and hence normal growth in the presence of D-ser. Specific transcriptional responses were induced in strains accumulating D-ser (WT EHEC and UPEC/NMEC mutants lacking the D-ser-responsive transcriptional activator DsdC), corroborating the notion that D-ser is an unfavourable metabolite if not metabolized. Importantly, many of the UPEC-associated transcriptome alterations correlate with published data on the urinary transcriptome, supporting the hypothesis that D-ser sensing forms a key part of urinary niche adaptation in this pathotype. Collectively, our results demonstrate distinct pleiotropic responses to a common metabolite in diverse E. coli pathotypes, with important implications for niche selectivity. Importance The pathogenic Escherichia coli comprise a group of highly specialized bacteria, some of which are capable of disseminating from the intestine and causing disease at other sites within the human host. Chemicals (metabolites) derived from the host and other microorganisms shape the behaviour of E. coli in different environments. Here we investigate the changes in gene expression that occur in E. coli strains capable (UPEC and NMEC) and incapable (EHEC) of metabolizing D-ser – a metabolite specifically enriched in the urine and in regions of the brain. We show that EHEC, UPEC and NMEC – distinct pathotypes associated with disease in the gut, bladder and brain, respectively, respond in a distinct manner to D-ser. Many of the genes affected by D-ser have been shown to be important during disease, highlighting the importance of varied responses to this common signal in host infection.