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.
View: Text | PDF
Research Article Inflammation Microbiology

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

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

×

Figure 2

In vivo response to urinary tract infection in C57BL/6 mice, comparing E. coli SN25 to 83972.

Options: View larger image (or click on image) Download as PowerPoint
In vivo response to urinary tract infection in C57BL/6 mice, comparing E...
(A) Mucosal Pol II phosphorylation at Ser2 (Pol II-p) was inhibited by E. coli 83972 but not by E. coli SN25. Pol II-p staining is indicated by the arrows. (B) Urine bacterial counts and neutrophil numbers were higher in E. coli SN25–infected mice after 24 hours (PMNs, polymorphonuclear leukocytes; CFU, colony forming unit), as well as (C) tissue neutrophil staining. Data are representative of 2 independent experiments and are presented as mean ± SEM (n = 5 mice). Scale bars: 50 μm. *P < 0.05, **P < 0.01 compared with control by Kruskal-Wallis test with Dunn’s multiple-comparison test. See also Figure 8 and Supplemental Figure 1.