Infection with uropathogenic E. coli induces dynamic epigenetic reprogramming of innate immunity

What is it about?

Innate immunity-related genes in humans are activated during urinary tract infections (UTIs) caused by pathogenic strains of Escherichia coli but are suppressed by commensals. Epigenetic mechanisms play a pivotal role in the regulation of gene expression in response to environmental stimuli. To determine whether epigenetic mechanisms can explain the different behaviors of pathogenic and commensal bacteria, we infected larvae of the greater wax moth Galleria mellonella, a widely-used model insect host, with a uropathogenic E. coli (UPEC) strain that causes symptomatic UTIs in humans or a commensal-like strain that causes asymptomatic bacteriuria (ABU). Infection with the UPEC strain (CFT073) was more lethal to larvae than the attenuated ABU strain (83972) due to the recognition of each strain by different Toll-like receptors, ultimately leading to differential DNA/RNA methylation and histone acetylation. We used next-generation sequencing and RT-PCR to correlate epigenetic changes with the induction of innate immunity-related genes. Transcriptomic analysis of G. mellonella larvae infected with E. coli strains CFT073 and 83972 revealed strain-specific variations in the class and expression levels of genes encoding antimicrobial peptides, cytokines, and enzymes controlling DNA methylation and histone acetylation. Our results provide evidence for the differential epigenetic regulation of transcriptional reprogramming by UPEC and ABU strains of E. coli in G. mellonella larvae, which may be relevant to understanding the different behavior of these bacterial strains in the human urinary tract.

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Why is it important?

Uropathogenic E. coli (UPEC) are the main agents responsible for uncomplicated urinary tract infections in humans and have evolved into strains that behave like commensals in the human urinary tract, thus causing asymptomatic bacteriuria (ABU). UPEC pathogenesis causes the strong induction of innate immunity-related genes that are usually suppressed by ABU strains. Epigenetic mechanisms control gene expression, and may thus influence innate immunity during ABU and UPEC infections. To address this hypothesis, we infected the model insect host Galleria mellonella with UPEC or ABU strains. and monitored larval survival. We found thatLarval survival was determined by the pathogenicity of the infecting strains, revealing a correlation between strain-specific innate immunity-related gene expression, and the epigenetic mechanisms of histone acetylation and DNA methylation. Our data confirm that differential epigenetic mechanisms in G. mellonella larvae regulate the transcriptional activation of innate immunity genes to distinguish between UPEC and ABU strains. , and tThis may improve our understanding of the corresponding mechanisms in the human urinary tract.