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.
Bibliographical noteFunding Information:
The authors thank Björn Nilsson, Division of Hematology and Transfusion Medicine, Lund University, for critical reading of the manuscript. The mass spectrometry was in collaboration with Charlotte Welinder at the Center for Translational Proteomics at the Medical Faculty and Region Skåne, Lund University, and Sven Kjellström and Simon Ekström at BioMS, the Swedish National Infrastructure for Biological Mass Spectrometry at Lund University. We gratefully acknowledge the support of the Swedish Medical Research Council, the European Research Council INFECT-ERA II program (The Nice Bug Consortium), the Swedish Cancer Society, the Medical Faculty at Lund University, the Söderberg and Österlund Foundations, the Sharon D Lund foundation, the Royal Physiographic Society, the HJ Forssman Foundation for Medical Research, and the Lundberg Foundation. The Dobrindt group at the University of Münster was supported by the German Research Foundation (CRC 1009/2, B05) and the Federal Ministry for Education and Research (grant no. 031L0007B). The Chen group at the National University of Singapore was supported by the Singapore Ministry of Health’s National Medical Research Council (NMRC/CIRG/1467/2017) and the Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR). Support for the Svanborg group was further provided from the European Union’s Horizon 2020 research and innovation program under grant agreement no. 954360.
© 2021, American Society for Clinical Investigation.
Copyright 2021 Elsevier B.V., All rights reserved.
Subject classification (UKÄ)
- Microbiology in the medical area
- Cell and Molecular Biology