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.

Molecular Analysis of Asymptomatic Bacteriuria Escherichia coli Strain VR50 Reveals Adaptation to the Urinary Tract by Gene Acquisition

“…This property may be associated with the ability of E. coli VR50 to colonize the bladder in high numbers without provoking a host inflammatory response and is consistent with the low IL-6 response observed in individuals deliberately colonized with E. coli 83972 (89). It remains to be determined if VR50 is able to suppress RNA polymerase II-dependent host gene expression, as has been reported recently for E. coli 83972 (19). Furthermore, host genetic variation that leads to suppression of the innate immune response to UTI (e.g., via Toll-like receptor 4 [TLR4] promoter polymorphisms) also contributes to protection against symptomatic disease in some ABU patients (90)(91)(92)(93).…”

“…Thus, the ancestor of E. coli 83972, which belongs to the B2 clonal group, was most likely a virulent UPEC strain that has become attenuated (18). Recently, E. coli 83972 adaptation to the human urinary tract has also been linked to its ability to suppress RNA polymerase II-dependent host gene expression following human bladder colonization, thereby preventing the activation of host proinflammatory responses during infection (19).…”

Human Microbiota Characterization in the Course of Renal Transplantation

“…It will be important to test whether such low level of colonization is associated with clinical symptoms, immunosuppressive regimen, renal function, on-going allograft inflammation as noted by protocol biopsies, or the eventual occurrence of polyoma BK virus nephropathy. Last, it is possible that some microbial species are commensals that stimulate a protective urinary mucosal response and that their presence is a sign of health rather than dysfunction (24).…”

Microbiome Disturbances and Autism Spectrum Disorders

“…Microbiota appear to orchestrate other host epimutations, such as chromatin rearrangements, alterations in noncoding RNAs, and RNA splicing factors (Bierne et al, 2012). One study suggests that pathogenic bacteria might usurp control of host gene expression by broadly suppressing RNA polymerase II, an enzyme required for synthesis of coding and noncoding RNAs (Lutay et al, 2013). Intriguingly, there has been recent evidence that some endosymbiotic bacteria produce small noncoding RNAs with the potential to exert cross-kingdom communication and affect host processes (Mayoral et al, 2014).…”