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Active bacterial modification of the host environment through RNA polymerase II inhibition
Inès Ambite, … , Ulrich Dobrindt, Catharina Svanborg
Inès Ambite, … , Ulrich Dobrindt, Catharina Svanborg
Published December 15, 2020
Citation Information: J Clin Invest. 2021;131(4):e140333. https://doi.org/10.1172/JCI140333.
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Research Article Inflammation Microbiology Article has an altmetric score of 28

Active bacterial modification of the host environment through RNA polymerase II inhibition

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Abstract

Unlike pathogens, which attack the host, commensal bacteria create a state of friendly coexistence. Here, we identified a mechanism of bacterial adaptation to the host niche, where they reside. Asymptomatic carrier strains were shown to inhibit RNA polymerase II (Pol II) in host cells by targeting Ser2 phosphorylation, a step required for productive mRNA elongation. Assisted by a rare, spontaneous loss-of-function mutant from a human carrier, the bacterial NlpD protein was identified as a Pol II inhibitor. After internalization by host cells, NlpD was shown to target constituents of the Pol II phosphorylation complex (RPB1 and PAF1C), attenuating host gene expression. Therapeutic efficacy of a recombinant NlpD protein was demonstrated in a urinary tract infection model, by reduced tissue pathology, accelerated bacterial clearance, and attenuated Pol II–dependent gene expression. The findings suggest an intriguing, evolutionarily conserved mechanism for bacterial modulation of host gene expression, with a remarkable therapeutic potential.

Authors

Inès Ambite, Nina A. Filenko, Elisabed Zaldastanishvili, Daniel S.C. Butler, Thi Hien Tran, Arunima Chaudhuri, Parisa Esmaeili, Shahram Ahmadi, Sanchari Paul, Björn Wullt, Johannes Putze, Swaine L. Chen, Ulrich Dobrindt, Catharina Svanborg

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Figure 1

Bacterial inhibition of Pol II phosphorylation.

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Bacterial inhibition of Pol II phosphorylation.
(A and B) Identification...
(A and B) Identification of E. coli SN25 as a loss-of-function mutant. Pol II Ser2 phosphorylation was quantified in human kidney cells infected with the ABU strain E. coli 83972 or E. coli SN25, a re-isolate from a human carrier of E. coli 83972. (A) Confocal microscopy and (B) flow cytometry. Nuclei were counterstained with DRAQ5. Histograms show quantification of fluorescence intensity. Scale bar: 10 μm. Data are presented as mean ± SEM (n = 3–6 experiments). *P < 0.05, **P < 0.01 compared with PBS control by Kruskal-Wallis test with Dunn’s multiple-comparison test. (C and D) Comparative gene expression analysis of host cells infected with E. coli 83972 or SN25. (C) Heatmap: >500 genes were regulated exclusively in response to E. coli SN25. (D) E. coli SN25 activated innate immune response genes more efficiently than E. coli 83972. Data are representative of 2 independent experiments; fold change (FC) > 2.0 compared with PBS control.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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