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

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

doi:10.1172/JCI140333

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

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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	e140333
Number of pages	17
Journal	Journal of Clinical Investigation
Volume	131
Issue number	4
DOIs	https://doi.org/10.1172/JCI140333
Publication status	Published - 2021 Feb 15

Bibliographical note

Funding 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.

Publisher Copyright:
© 2021, American Society for Clinical Investigation.

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

Subject classification (UKÄ)

Microbiology in the medical area
Cell and Molecular Biology

Free keywords

Inflammation
Microbiology
Immunotherapy
Transcription

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10.1172/JCI140333

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Ambite, I., Filenko, N. A., Zaldastanishvili, E., Butler, D. S. C., Tran, T. H., Chaudhuri, A., Esmaeili, P., Ahmadi, S., Paul, S., Wullt, B., Putze, J., Chen, S. L., Dobrindt, U., & Svanborg, C. (2021). Active bacterial modification of the host environment through RNA polymerase II inhibition. Journal of Clinical Investigation, 131(4), Article e140333. https://doi.org/10.1172/JCI140333

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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.",

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author = "In{\`e}s Ambite and Filenko, {Nina A.} and Elisabed Zaldastanishvili and Butler, {Daniel S.C.} and Tran, {Thi Hien} and Arunima Chaudhuri and Parisa Esmaeili and Shahram Ahmadi and Sanchari Paul and Bj{\"o}rn Wullt and Johannes Putze and Chen, {Swaine L.} and Ulrich Dobrindt and Catharina Svanborg",

note = "Funding Information: The authors thank Bj{\"o}rn 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 Sk{\aa}ne, Lund University, and Sven Kjellstr{\"o}m and Simon Ekstr{\"o}m 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 S{\"o}derberg and {\"O}sterlund 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 M{\"u}nster 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{\textquoteright}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{\textquoteright}s Horizon 2020 research and innovation program under grant agreement no. 954360. Publisher Copyright: {\textcopyright} 2021, American Society for Clinical Investigation. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

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doi = "10.1172/JCI140333",

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T1 - Active bacterial modification of the host environment through RNA polymerase II inhibition

AU - Ambite, Inès

AU - Filenko, Nina A.

AU - Zaldastanishvili, Elisabed

AU - Butler, Daniel S.C.

AU - Tran, Thi Hien

AU - Chaudhuri, Arunima

AU - Esmaeili, Parisa

AU - Ahmadi, Shahram

AU - Paul, Sanchari

AU - Wullt, Björn

AU - Putze, Johannes

AU - Chen, Swaine L.

AU - Dobrindt, Ulrich

AU - Svanborg, Catharina

N1 - Funding 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. Publisher Copyright: © 2021, American Society for Clinical Investigation. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/2/15

Y1 - 2021/2/15

N2 - 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.

AB - 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.

KW - Inflammation

KW - Microbiology

KW - Immunotherapy

KW - Transcription

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DO - 10.1172/JCI140333

M3 - Article

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SN - 0021-9738

VL - 131

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 4

M1 - e140333

ER -

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

Abstract

Bibliographical note

Subject classification (UKÄ)

Free keywords

Access to Document

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