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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 4

Suppression of Pol II phosphorylation by E. coli 83972

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Suppression of Pol II phosphorylation by E. coli 83972
.(A) Active Ser2 ...
(A) Active Ser2 phosphorylated Pol II was stained using monoclonal primary human phospho CTD Ser2 antibodies and peroxidase-labeled secondary antibodies (brown). E. coli 83972 markedly suppressed Pol II phosphorylation compared with uninfected or CFT073-infected human kidney cells (A498). E. coli CFT073 had a nonsuppressive effect. (B) Inhibition by E. coli 83972 of Pol II phosphorylation in primary human kidney cells (HRTEC) compared with uninfected or CFT073-infected cells. (C) The specific Pol II inhibitor DRB (60 μM) abrogated Pol II phosphorylation in response to E. coli CFT073 compared with A498 cells without an inhibitor. For dose-dependent inhibition of Pol II phosphorylation in uninfected A498 cells, see Supplemental Figure 7A. (D) Competition between E. coli CFT073 and 83972 in A498 cells. E. coli 83972 inhibited Pol II phosphorylation in the presence of E. coli CFT073. (A and C) Scale bars: 50 μm and 10 μm (insets). #P = compared with medium control; ##P = compared with CFT073-infected cells; χ2 test for independence.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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