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Bacterial control of host gene expression through RNA polymerase II
Nataliya Lutay, … , Björn Wullt, Catharina Svanborg
Nataliya Lutay, … , Björn Wullt, Catharina Svanborg
Published May 24, 2013
Citation Information: J Clin Invest. 2013;123(6):2366-2379. https://doi.org/10.1172/JCI66451.
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Research Article

Bacterial control of host gene expression through RNA polymerase II

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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

Nataliya Lutay, Ines Ambite, Jenny Grönberg Hernandez, Gustav Rydström, Bryndís Ragnarsdóttir, Manoj Puthia, Aftab Nadeem, Jingyao Zhang, Petter Storm, Ulrich Dobrindt, Björn Wullt, Catharina Svanborg

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Figure 5

Pathogen-specific signaling in infected A498 cells.

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Pathogen-specific signaling in infected A498 cells.
(A) Suppression by E...
(A) Suppression by E. coli 83972 (right panels) of genes in the TLR4/CREB/IRF3/7 and type 1 IFN pathways. For log2 fold changes of individual genes, see Supplemental Table 3. Activation by E. coli CFT073 is shown for comparison. Increased expression (red), reduced expression (green), and no change (gray). Color intensity reflects the fold change. (B) Phosphorylation of molecules in the TLR4/CREB/IRF3/7 signaling pathway examined by phosphoarray analysis of whole-cell extracts from E. coli 83972-infected A498 cells. (C) The ABU strain suppressed the phosphorylation of 7 targets compared with uninfected cells. Quantification based on pixel intensities of phosphorylated targets. Cutoff is set at a fold change less than –1.5 or greater than 1.5.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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