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ResearchIn-Press PreviewImmunologyInfectious disease Open Access | 10.1172/JCI158630

Poly(ADP)ribose polymerase 9 mediates early protection against Mycobacterium tuberculosis infection by regulating type I IFN production

Shyamala Thirunavukkarasu,1 Mushtaq Ahmed,1 Bruce A. Rosa,2 Mark Boothby,3 Sung Hoon Cho,3 Javier Rangel-Moreno,5 Stanley K. Mbandi,6 Valérie Schreiber,7 Ananya Gupta,8 Joaquin Zúñiga,9 Makedonka Mitreva,2 Deepak Kaushal,10 Thomas J. Scriba,6 and Shabaana A. Khader1

1Department of Molecular Microbiology, Washington University, St. Louis, St. Louis, United States of America

2Washington University in St Louis, The McDonnell Genome Institute, St. Louis, United States of America

3Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, United States of America

4Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, United Kingdom

5Department of Medicine, University of Rochester Medical Center, Rochester, United States of America

6South African Tuberculosis Vaccine Initiative, University of Cape Town, Cape Town, South Africa

7Biotechnology and Cell Signalling, CNRS/ UMR 7242, Illkirch, France

8Department of Molecular Microbiology, The University of Chicago, Chicago, United States of America

9Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Mexico City, Mexico

10Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, United States of America

Find articles by Thirunavukkarasu, S. in: JCI | PubMed | Google Scholar

1Department of Molecular Microbiology, Washington University, St. Louis, St. Louis, United States of America

2Washington University in St Louis, The McDonnell Genome Institute, St. Louis, United States of America

3Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, United States of America

4Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, United Kingdom

5Department of Medicine, University of Rochester Medical Center, Rochester, United States of America

6South African Tuberculosis Vaccine Initiative, University of Cape Town, Cape Town, South Africa

7Biotechnology and Cell Signalling, CNRS/ UMR 7242, Illkirch, France

8Department of Molecular Microbiology, The University of Chicago, Chicago, United States of America

9Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Mexico City, Mexico

10Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, United States of America

Find articles by Ahmed, M. in: JCI | PubMed | Google Scholar |

1Department of Molecular Microbiology, Washington University, St. Louis, St. Louis, United States of America

2Washington University in St Louis, The McDonnell Genome Institute, St. Louis, United States of America

3Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, United States of America

4Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, United Kingdom

5Department of Medicine, University of Rochester Medical Center, Rochester, United States of America

6South African Tuberculosis Vaccine Initiative, University of Cape Town, Cape Town, South Africa

7Biotechnology and Cell Signalling, CNRS/ UMR 7242, Illkirch, France

8Department of Molecular Microbiology, The University of Chicago, Chicago, United States of America

9Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Mexico City, Mexico

10Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, United States of America

Find articles by Rosa, B. in: JCI | PubMed | Google Scholar |

1Department of Molecular Microbiology, Washington University, St. Louis, St. Louis, United States of America

2Washington University in St Louis, The McDonnell Genome Institute, St. Louis, United States of America

3Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, United States of America

4Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, United Kingdom

5Department of Medicine, University of Rochester Medical Center, Rochester, United States of America

6South African Tuberculosis Vaccine Initiative, University of Cape Town, Cape Town, South Africa

7Biotechnology and Cell Signalling, CNRS/ UMR 7242, Illkirch, France

8Department of Molecular Microbiology, The University of Chicago, Chicago, United States of America

9Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Mexico City, Mexico

10Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, United States of America

Find articles by Boothby, M. in: JCI | PubMed | Google Scholar |

1Department of Molecular Microbiology, Washington University, St. Louis, St. Louis, United States of America

2Washington University in St Louis, The McDonnell Genome Institute, St. Louis, United States of America

3Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, United States of America

4Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, United Kingdom

5Department of Medicine, University of Rochester Medical Center, Rochester, United States of America

6South African Tuberculosis Vaccine Initiative, University of Cape Town, Cape Town, South Africa

7Biotechnology and Cell Signalling, CNRS/ UMR 7242, Illkirch, France

8Department of Molecular Microbiology, The University of Chicago, Chicago, United States of America

9Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Mexico City, Mexico

10Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, United States of America

Find articles by Cho, S. in: JCI | PubMed | Google Scholar |

1Department of Molecular Microbiology, Washington University, St. Louis, St. Louis, United States of America

2Washington University in St Louis, The McDonnell Genome Institute, St. Louis, United States of America

3Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, United States of America

4Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, United Kingdom

5Department of Medicine, University of Rochester Medical Center, Rochester, United States of America

6South African Tuberculosis Vaccine Initiative, University of Cape Town, Cape Town, South Africa

7Biotechnology and Cell Signalling, CNRS/ UMR 7242, Illkirch, France

8Department of Molecular Microbiology, The University of Chicago, Chicago, United States of America

9Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Mexico City, Mexico

10Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, United States of America

Find articles by Rangel-Moreno, J. in: JCI | PubMed | Google Scholar |

1Department of Molecular Microbiology, Washington University, St. Louis, St. Louis, United States of America

2Washington University in St Louis, The McDonnell Genome Institute, St. Louis, United States of America

3Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, United States of America

4Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, United Kingdom

5Department of Medicine, University of Rochester Medical Center, Rochester, United States of America

6South African Tuberculosis Vaccine Initiative, University of Cape Town, Cape Town, South Africa

7Biotechnology and Cell Signalling, CNRS/ UMR 7242, Illkirch, France

8Department of Molecular Microbiology, The University of Chicago, Chicago, United States of America

9Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Mexico City, Mexico

10Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, United States of America

Find articles by Mbandi, S. in: JCI | PubMed | Google Scholar |

1Department of Molecular Microbiology, Washington University, St. Louis, St. Louis, United States of America

2Washington University in St Louis, The McDonnell Genome Institute, St. Louis, United States of America

3Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, United States of America

4Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, United Kingdom

5Department of Medicine, University of Rochester Medical Center, Rochester, United States of America

6South African Tuberculosis Vaccine Initiative, University of Cape Town, Cape Town, South Africa

7Biotechnology and Cell Signalling, CNRS/ UMR 7242, Illkirch, France

8Department of Molecular Microbiology, The University of Chicago, Chicago, United States of America

9Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Mexico City, Mexico

10Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, United States of America

Find articles by Schreiber, V. in: JCI | PubMed | Google Scholar |

1Department of Molecular Microbiology, Washington University, St. Louis, St. Louis, United States of America

2Washington University in St Louis, The McDonnell Genome Institute, St. Louis, United States of America

3Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, United States of America

4Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, United Kingdom

5Department of Medicine, University of Rochester Medical Center, Rochester, United States of America

6South African Tuberculosis Vaccine Initiative, University of Cape Town, Cape Town, South Africa

7Biotechnology and Cell Signalling, CNRS/ UMR 7242, Illkirch, France

8Department of Molecular Microbiology, The University of Chicago, Chicago, United States of America

9Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Mexico City, Mexico

10Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, United States of America

Find articles by Gupta, A. in: JCI | PubMed | Google Scholar

1Department of Molecular Microbiology, Washington University, St. Louis, St. Louis, United States of America

2Washington University in St Louis, The McDonnell Genome Institute, St. Louis, United States of America

3Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, United States of America

4Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, United Kingdom

5Department of Medicine, University of Rochester Medical Center, Rochester, United States of America

6South African Tuberculosis Vaccine Initiative, University of Cape Town, Cape Town, South Africa

7Biotechnology and Cell Signalling, CNRS/ UMR 7242, Illkirch, France

8Department of Molecular Microbiology, The University of Chicago, Chicago, United States of America

9Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Mexico City, Mexico

10Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, United States of America

Find articles by Zúñiga, J. in: JCI | PubMed | Google Scholar |

1Department of Molecular Microbiology, Washington University, St. Louis, St. Louis, United States of America

2Washington University in St Louis, The McDonnell Genome Institute, St. Louis, United States of America

3Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, United States of America

4Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, United Kingdom

5Department of Medicine, University of Rochester Medical Center, Rochester, United States of America

6South African Tuberculosis Vaccine Initiative, University of Cape Town, Cape Town, South Africa

7Biotechnology and Cell Signalling, CNRS/ UMR 7242, Illkirch, France

8Department of Molecular Microbiology, The University of Chicago, Chicago, United States of America

9Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Mexico City, Mexico

10Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, United States of America

Find articles by Mitreva, M. in: JCI | PubMed | Google Scholar

1Department of Molecular Microbiology, Washington University, St. Louis, St. Louis, United States of America

2Washington University in St Louis, The McDonnell Genome Institute, St. Louis, United States of America

3Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, United States of America

4Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, United Kingdom

5Department of Medicine, University of Rochester Medical Center, Rochester, United States of America

6South African Tuberculosis Vaccine Initiative, University of Cape Town, Cape Town, South Africa

7Biotechnology and Cell Signalling, CNRS/ UMR 7242, Illkirch, France

8Department of Molecular Microbiology, The University of Chicago, Chicago, United States of America

9Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Mexico City, Mexico

10Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, United States of America

Find articles by Kaushal, D. in: JCI | PubMed | Google Scholar |

1Department of Molecular Microbiology, Washington University, St. Louis, St. Louis, United States of America

2Washington University in St Louis, The McDonnell Genome Institute, St. Louis, United States of America

3Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, United States of America

4Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, United Kingdom

5Department of Medicine, University of Rochester Medical Center, Rochester, United States of America

6South African Tuberculosis Vaccine Initiative, University of Cape Town, Cape Town, South Africa

7Biotechnology and Cell Signalling, CNRS/ UMR 7242, Illkirch, France

8Department of Molecular Microbiology, The University of Chicago, Chicago, United States of America

9Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Mexico City, Mexico

10Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, United States of America

Find articles by Scriba, T. in: JCI | PubMed | Google Scholar |

1Department of Molecular Microbiology, Washington University, St. Louis, St. Louis, United States of America

2Washington University in St Louis, The McDonnell Genome Institute, St. Louis, United States of America

3Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, United States of America

4Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, United Kingdom

5Department of Medicine, University of Rochester Medical Center, Rochester, United States of America

6South African Tuberculosis Vaccine Initiative, University of Cape Town, Cape Town, South Africa

7Biotechnology and Cell Signalling, CNRS/ UMR 7242, Illkirch, France

8Department of Molecular Microbiology, The University of Chicago, Chicago, United States of America

9Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Mexico City, Mexico

10Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, United States of America

Find articles by Khader, S. in: JCI | PubMed | Google Scholar |

Published May 18, 2023 - More info

J Clin Invest. https://doi.org/10.1172/JCI158630.
Copyright © 2023, Thirunavukkarasu et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published May 18, 2023 - Version history
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Abstract

The ADP ribosyl transferases (PARPs 1–17) regulate diverse cellular processes, including DNA damage repair. PARPs are classified based on their ability to catalyze poly-ADP-ribosylation (PARylation) or mono-ADP-ribosylation (MARylation). While PARP9 mRNA expression is significantly increased in progressive human tuberculosis (TB), its participation in host immunity to TB is unknown. Here, we show that PARP9 mRNA encoding the MARylating PARP9 enzyme is upregulated during TB in humans and mice and provide evidence of a critical modulatory role for PARP9 in DNA damage, cGAS and type I IFN production during TB. Thus, Parp9-deficient mice are susceptible to Mtb infection and exhibit increased TB disease, cGAS expression, cGAMP and type I IFN production along with upregulation of complement and coagulation pathways. Enhanced Mtb susceptibility is type I IFN-dependent, as blockade of IFNAR signaling reversed the enhanced susceptibility of Parp9-/- mice. Thus, in sharp contrast with PARP9 enhancement of type I IFN production in viral infections, this member of the MAR family plays a protective role by limiting type I IFN responses during TB.

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