title: Bacterial control of host gene expression  through RNA polymerase II.
abstract: The normal flora furnishes the host with ecological barriers that prevent pathogen attack while maintaining tissue homeostasis. Urinary tract infections (UTIs) constitute a highly relevant model of microbial adaptation in which some patients infected with Escherichia coli develop acute pyelonephritis, while other patients with bacteriuria exhibit an asymptomatic carrier state similar to bacterial commensalism. It remains unclear if the lack of destructive inflammation merely reflects low virulence or if carrier strains actively inhibit disease-associated responses in the host. Here, we identify a new mechanism of bacterial adaptation through broad suppression of RNA polymerase II–dependent (Pol II–dependent) host gene expression. Over 60% of all genes were suppressed 24 hours after human inoculation with the prototype asymptomatic bacteriuria (ABU) strain E. coli 83972, and inhibition was verified by infection of human cells. Specific repressors and activators of Pol II–dependent transcription were modified, Pol II phosphorylation was inhibited, and pathogen-specific signaling was suppressed in cell lines and inoculated patients. An increased frequency of strains inhibiting Pol II was epidemiologically verified in ABU and fecal strains compared with acute pyelonephritis, and a Pol II antagonist suppressed the disease-associated host response. These results suggest that by manipulating host gene expression, ABU strains promote tissue integrity while inhibiting pathology. Such bacterial modulation of host gene expression may be essential to sustain asymptomatic bacterial carriage by ensuring that potentially destructive immune activation will not occur.
authors.affiliation: Department of Microbiology, Immunology and Glycobiology, Institute of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Nataliya
authors.initials: N
authors.lastname: Lutay
authors.forename: Ines
authors.initials: I
authors.lastname: Ambite
authors.forename: Jenny
authors.initials: J
authors.lastname: Grönberg Hernandez
authors.forename: Gustav
authors.initials: G
authors.lastname: Rydström
authors.forename: Bryndís
authors.initials: B
authors.lastname: Ragnarsdóttir
authors.forename: Manoj
authors.initials: M
authors.lastname: Puthia
authors.forename: Aftab
authors.initials: A
authors.lastname: Nadeem
authors.forename: Jingyao
authors.initials: J
authors.lastname: Zhang
authors.forename: Petter
authors.initials: P
authors.lastname: Storm
authors.forename: Ulrich
authors.initials: U
authors.lastname: Dobrindt
authors.forename: Björn
authors.initials: B
authors.lastname: Wullt
authors.forename: Catharina
authors.initials: C
authors.lastname: Svanborg
mesh_terms: D058345:Asymptomatic Infections; D001437:Bacteriuria / Q000201:enzymology* / Q000276:immunology / Q000382:microbiology; D002478:Cells, Cultured; D004794:Enzyme Repression; D004847:Epithelial Cells / Q000201:enzymology / Q000276:immunology / Q000382:microbiology; D004926:Escherichia coli / Q000276:immunology / Q000502:physiology; D004927:Escherichia coli Infections / Q000201:enzymology* / Q000276:immunology / Q000382:microbiology; D005243:Feces / Q000382:microbiology; D015870:Gene Expression; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011704:Pyelonephritis / Q000201:enzymology / Q000276:immunology / Q000382:microbiology; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D014552:Urinary Tract Infections / Q000201:enzymology* / Q000276:immunology / Q000382:microbiology
chemical_list: D012319:RNA Polymerase II