Research ArticleInfectious diseaseMicrobiology Open Access | 10.1172/JCI161944

Melissa Bedard,1 Sanne van der Niet,2 Elliott M. Bernard,3 Gregory Babunovic,1,4 Tan-Yun Cheng,1 Beren Aylan,3 Anita E. Grootemaat,2 Sahadevan Raman,1 Laure Botella,3 Eri Ishikawa,5 Mary P. O’Sullivan,6 Seónadh O’Leary,6 Jacob A. Mayfield,1 Jeffrey Buter,7 Adriaan J. Minnaard,7 Sarah M. Fortune,4 Leon O. Murphy,8 Daniel S. Ory,8 Joseph Keane,6 Sho Yamasaki,5 Maximiliano G. Gutierrez,3 Nicole van der Wel,2 and D. Branch Moody1

1Division of Rheumatology, Immunity and Inflammation, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

2Electron Microscopy Centre Amsterdam, Amsterdam University Medical Centre, Amsterdam, Netherlands.

3Host-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, London, United Kingdom.

4Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

5Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.

6Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James’s Hospital, Trinity College, Dublin, Ireland.

7Department of Chemical Biology, Stratingh Institute for Chemistry, Groningen, Netherlands.

8Casma Therapeutics, Cambridge, Massachusetts, USA.

Address correspondence to: D. Branch Moody, 60 Fenwood Road, Room 6006K, Boston, Massachusetts 02110, USA. Email: bmoody@bwh.harvard.edu. Or to: Maximiliano G Gutierrez, 1 Midland Road, London, NW1 1AT, United Kingdom. Email: max.g@crick.ac.uk. Or to: Nicole van Der Wel, Meibergdreef 9, 1105AZ, Amsterdam, Netherlands. Email: n.n.vanderwel@amsterdamumc.nl.

Authorship note: MB, SVDN, EMB, and GB contributed equally to this work.

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

1Division of Rheumatology, Immunity and Inflammation, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

2Electron Microscopy Centre Amsterdam, Amsterdam University Medical Centre, Amsterdam, Netherlands.

3Host-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, London, United Kingdom.

4Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

5Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.

6Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James’s Hospital, Trinity College, Dublin, Ireland.

7Department of Chemical Biology, Stratingh Institute for Chemistry, Groningen, Netherlands.

8Casma Therapeutics, Cambridge, Massachusetts, USA.

Address correspondence to: D. Branch Moody, 60 Fenwood Road, Room 6006K, Boston, Massachusetts 02110, USA. Email: bmoody@bwh.harvard.edu. Or to: Maximiliano G Gutierrez, 1 Midland Road, London, NW1 1AT, United Kingdom. Email: max.g@crick.ac.uk. Or to: Nicole van Der Wel, Meibergdreef 9, 1105AZ, Amsterdam, Netherlands. Email: n.n.vanderwel@amsterdamumc.nl.

Authorship note: MB, SVDN, EMB, and GB contributed equally to this work.

Find articles by van der Niet, S. in: JCI | PubMed | Google Scholar

1Division of Rheumatology, Immunity and Inflammation, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

2Electron Microscopy Centre Amsterdam, Amsterdam University Medical Centre, Amsterdam, Netherlands.

3Host-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, London, United Kingdom.

4Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

5Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.

6Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James’s Hospital, Trinity College, Dublin, Ireland.

7Department of Chemical Biology, Stratingh Institute for Chemistry, Groningen, Netherlands.

8Casma Therapeutics, Cambridge, Massachusetts, USA.

Address correspondence to: D. Branch Moody, 60 Fenwood Road, Room 6006K, Boston, Massachusetts 02110, USA. Email: bmoody@bwh.harvard.edu. Or to: Maximiliano G Gutierrez, 1 Midland Road, London, NW1 1AT, United Kingdom. Email: max.g@crick.ac.uk. Or to: Nicole van Der Wel, Meibergdreef 9, 1105AZ, Amsterdam, Netherlands. Email: n.n.vanderwel@amsterdamumc.nl.

Authorship note: MB, SVDN, EMB, and GB contributed equally to this work.

Find articles by Bernard, E. in: JCI | PubMed | Google Scholar |

1Division of Rheumatology, Immunity and Inflammation, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

2Electron Microscopy Centre Amsterdam, Amsterdam University Medical Centre, Amsterdam, Netherlands.

3Host-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, London, United Kingdom.

4Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

5Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.

6Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James’s Hospital, Trinity College, Dublin, Ireland.

7Department of Chemical Biology, Stratingh Institute for Chemistry, Groningen, Netherlands.

8Casma Therapeutics, Cambridge, Massachusetts, USA.

Address correspondence to: D. Branch Moody, 60 Fenwood Road, Room 6006K, Boston, Massachusetts 02110, USA. Email: bmoody@bwh.harvard.edu. Or to: Maximiliano G Gutierrez, 1 Midland Road, London, NW1 1AT, United Kingdom. Email: max.g@crick.ac.uk. Or to: Nicole van Der Wel, Meibergdreef 9, 1105AZ, Amsterdam, Netherlands. Email: n.n.vanderwel@amsterdamumc.nl.

Authorship note: MB, SVDN, EMB, and GB contributed equally to this work.

Find articles by Babunovic, G. in: JCI | PubMed | Google Scholar

1Division of Rheumatology, Immunity and Inflammation, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

2Electron Microscopy Centre Amsterdam, Amsterdam University Medical Centre, Amsterdam, Netherlands.

3Host-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, London, United Kingdom.

4Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

5Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.

6Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James’s Hospital, Trinity College, Dublin, Ireland.

7Department of Chemical Biology, Stratingh Institute for Chemistry, Groningen, Netherlands.

8Casma Therapeutics, Cambridge, Massachusetts, USA.

Address correspondence to: D. Branch Moody, 60 Fenwood Road, Room 6006K, Boston, Massachusetts 02110, USA. Email: bmoody@bwh.harvard.edu. Or to: Maximiliano G Gutierrez, 1 Midland Road, London, NW1 1AT, United Kingdom. Email: max.g@crick.ac.uk. Or to: Nicole van Der Wel, Meibergdreef 9, 1105AZ, Amsterdam, Netherlands. Email: n.n.vanderwel@amsterdamumc.nl.

Authorship note: MB, SVDN, EMB, and GB contributed equally to this work.

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

1Division of Rheumatology, Immunity and Inflammation, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

2Electron Microscopy Centre Amsterdam, Amsterdam University Medical Centre, Amsterdam, Netherlands.

3Host-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, London, United Kingdom.

4Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

5Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.

6Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James’s Hospital, Trinity College, Dublin, Ireland.

7Department of Chemical Biology, Stratingh Institute for Chemistry, Groningen, Netherlands.

8Casma Therapeutics, Cambridge, Massachusetts, USA.

Address correspondence to: D. Branch Moody, 60 Fenwood Road, Room 6006K, Boston, Massachusetts 02110, USA. Email: bmoody@bwh.harvard.edu. Or to: Maximiliano G Gutierrez, 1 Midland Road, London, NW1 1AT, United Kingdom. Email: max.g@crick.ac.uk. Or to: Nicole van Der Wel, Meibergdreef 9, 1105AZ, Amsterdam, Netherlands. Email: n.n.vanderwel@amsterdamumc.nl.

Authorship note: MB, SVDN, EMB, and GB contributed equally to this work.

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1Division of Rheumatology, Immunity and Inflammation, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

2Electron Microscopy Centre Amsterdam, Amsterdam University Medical Centre, Amsterdam, Netherlands.

3Host-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, London, United Kingdom.

4Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

5Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.

6Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James’s Hospital, Trinity College, Dublin, Ireland.

7Department of Chemical Biology, Stratingh Institute for Chemistry, Groningen, Netherlands.

8Casma Therapeutics, Cambridge, Massachusetts, USA.

Address correspondence to: D. Branch Moody, 60 Fenwood Road, Room 6006K, Boston, Massachusetts 02110, USA. Email: bmoody@bwh.harvard.edu. Or to: Maximiliano G Gutierrez, 1 Midland Road, London, NW1 1AT, United Kingdom. Email: max.g@crick.ac.uk. Or to: Nicole van Der Wel, Meibergdreef 9, 1105AZ, Amsterdam, Netherlands. Email: n.n.vanderwel@amsterdamumc.nl.

Authorship note: MB, SVDN, EMB, and GB contributed equally to this work.

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

1Division of Rheumatology, Immunity and Inflammation, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

2Electron Microscopy Centre Amsterdam, Amsterdam University Medical Centre, Amsterdam, Netherlands.

3Host-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, London, United Kingdom.

4Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

5Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.

6Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James’s Hospital, Trinity College, Dublin, Ireland.

7Department of Chemical Biology, Stratingh Institute for Chemistry, Groningen, Netherlands.

8Casma Therapeutics, Cambridge, Massachusetts, USA.

Address correspondence to: D. Branch Moody, 60 Fenwood Road, Room 6006K, Boston, Massachusetts 02110, USA. Email: bmoody@bwh.harvard.edu. Or to: Maximiliano G Gutierrez, 1 Midland Road, London, NW1 1AT, United Kingdom. Email: max.g@crick.ac.uk. Or to: Nicole van Der Wel, Meibergdreef 9, 1105AZ, Amsterdam, Netherlands. Email: n.n.vanderwel@amsterdamumc.nl.

Authorship note: MB, SVDN, EMB, and GB contributed equally to this work.

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1Division of Rheumatology, Immunity and Inflammation, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

2Electron Microscopy Centre Amsterdam, Amsterdam University Medical Centre, Amsterdam, Netherlands.

3Host-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, London, United Kingdom.

4Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

5Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.

6Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James’s Hospital, Trinity College, Dublin, Ireland.

7Department of Chemical Biology, Stratingh Institute for Chemistry, Groningen, Netherlands.

8Casma Therapeutics, Cambridge, Massachusetts, USA.

Address correspondence to: D. Branch Moody, 60 Fenwood Road, Room 6006K, Boston, Massachusetts 02110, USA. Email: bmoody@bwh.harvard.edu. Or to: Maximiliano G Gutierrez, 1 Midland Road, London, NW1 1AT, United Kingdom. Email: max.g@crick.ac.uk. Or to: Nicole van Der Wel, Meibergdreef 9, 1105AZ, Amsterdam, Netherlands. Email: n.n.vanderwel@amsterdamumc.nl.

Authorship note: MB, SVDN, EMB, and GB contributed equally to this work.

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1Division of Rheumatology, Immunity and Inflammation, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

2Electron Microscopy Centre Amsterdam, Amsterdam University Medical Centre, Amsterdam, Netherlands.

3Host-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, London, United Kingdom.

4Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

5Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.

6Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James’s Hospital, Trinity College, Dublin, Ireland.

7Department of Chemical Biology, Stratingh Institute for Chemistry, Groningen, Netherlands.

8Casma Therapeutics, Cambridge, Massachusetts, USA.

Address correspondence to: D. Branch Moody, 60 Fenwood Road, Room 6006K, Boston, Massachusetts 02110, USA. Email: bmoody@bwh.harvard.edu. Or to: Maximiliano G Gutierrez, 1 Midland Road, London, NW1 1AT, United Kingdom. Email: max.g@crick.ac.uk. Or to: Nicole van Der Wel, Meibergdreef 9, 1105AZ, Amsterdam, Netherlands. Email: n.n.vanderwel@amsterdamumc.nl.

Authorship note: MB, SVDN, EMB, and GB contributed equally to this work.

Find articles by Ishikawa, E. in: JCI | PubMed | Google Scholar

1Division of Rheumatology, Immunity and Inflammation, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

2Electron Microscopy Centre Amsterdam, Amsterdam University Medical Centre, Amsterdam, Netherlands.

3Host-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, London, United Kingdom.

4Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

5Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.

6Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James’s Hospital, Trinity College, Dublin, Ireland.

7Department of Chemical Biology, Stratingh Institute for Chemistry, Groningen, Netherlands.

8Casma Therapeutics, Cambridge, Massachusetts, USA.

Address correspondence to: D. Branch Moody, 60 Fenwood Road, Room 6006K, Boston, Massachusetts 02110, USA. Email: bmoody@bwh.harvard.edu. Or to: Maximiliano G Gutierrez, 1 Midland Road, London, NW1 1AT, United Kingdom. Email: max.g@crick.ac.uk. Or to: Nicole van Der Wel, Meibergdreef 9, 1105AZ, Amsterdam, Netherlands. Email: n.n.vanderwel@amsterdamumc.nl.

Authorship note: MB, SVDN, EMB, and GB contributed equally to this work.

Find articles by O’Sullivan, M. in: JCI | PubMed | Google Scholar |

1Division of Rheumatology, Immunity and Inflammation, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

2Electron Microscopy Centre Amsterdam, Amsterdam University Medical Centre, Amsterdam, Netherlands.

3Host-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, London, United Kingdom.

4Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

5Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.

6Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James’s Hospital, Trinity College, Dublin, Ireland.

7Department of Chemical Biology, Stratingh Institute for Chemistry, Groningen, Netherlands.

8Casma Therapeutics, Cambridge, Massachusetts, USA.

Address correspondence to: D. Branch Moody, 60 Fenwood Road, Room 6006K, Boston, Massachusetts 02110, USA. Email: bmoody@bwh.harvard.edu. Or to: Maximiliano G Gutierrez, 1 Midland Road, London, NW1 1AT, United Kingdom. Email: max.g@crick.ac.uk. Or to: Nicole van Der Wel, Meibergdreef 9, 1105AZ, Amsterdam, Netherlands. Email: n.n.vanderwel@amsterdamumc.nl.

Authorship note: MB, SVDN, EMB, and GB contributed equally to this work.

Find articles by O’Leary, S. in: JCI | PubMed | Google Scholar

1Division of Rheumatology, Immunity and Inflammation, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

2Electron Microscopy Centre Amsterdam, Amsterdam University Medical Centre, Amsterdam, Netherlands.

3Host-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, London, United Kingdom.

4Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

5Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.

6Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James’s Hospital, Trinity College, Dublin, Ireland.

7Department of Chemical Biology, Stratingh Institute for Chemistry, Groningen, Netherlands.

8Casma Therapeutics, Cambridge, Massachusetts, USA.

Address correspondence to: D. Branch Moody, 60 Fenwood Road, Room 6006K, Boston, Massachusetts 02110, USA. Email: bmoody@bwh.harvard.edu. Or to: Maximiliano G Gutierrez, 1 Midland Road, London, NW1 1AT, United Kingdom. Email: max.g@crick.ac.uk. Or to: Nicole van Der Wel, Meibergdreef 9, 1105AZ, Amsterdam, Netherlands. Email: n.n.vanderwel@amsterdamumc.nl.

Authorship note: MB, SVDN, EMB, and GB contributed equally to this work.

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

1Division of Rheumatology, Immunity and Inflammation, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

2Electron Microscopy Centre Amsterdam, Amsterdam University Medical Centre, Amsterdam, Netherlands.

3Host-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, London, United Kingdom.

4Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

5Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.

6Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James’s Hospital, Trinity College, Dublin, Ireland.

7Department of Chemical Biology, Stratingh Institute for Chemistry, Groningen, Netherlands.

8Casma Therapeutics, Cambridge, Massachusetts, USA.

Address correspondence to: D. Branch Moody, 60 Fenwood Road, Room 6006K, Boston, Massachusetts 02110, USA. Email: bmoody@bwh.harvard.edu. Or to: Maximiliano G Gutierrez, 1 Midland Road, London, NW1 1AT, United Kingdom. Email: max.g@crick.ac.uk. Or to: Nicole van Der Wel, Meibergdreef 9, 1105AZ, Amsterdam, Netherlands. Email: n.n.vanderwel@amsterdamumc.nl.

Authorship note: MB, SVDN, EMB, and GB contributed equally to this work.

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

1Division of Rheumatology, Immunity and Inflammation, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

2Electron Microscopy Centre Amsterdam, Amsterdam University Medical Centre, Amsterdam, Netherlands.

3Host-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, London, United Kingdom.

4Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

5Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.

6Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James’s Hospital, Trinity College, Dublin, Ireland.

7Department of Chemical Biology, Stratingh Institute for Chemistry, Groningen, Netherlands.

8Casma Therapeutics, Cambridge, Massachusetts, USA.

Address correspondence to: D. Branch Moody, 60 Fenwood Road, Room 6006K, Boston, Massachusetts 02110, USA. Email: bmoody@bwh.harvard.edu. Or to: Maximiliano G Gutierrez, 1 Midland Road, London, NW1 1AT, United Kingdom. Email: max.g@crick.ac.uk. Or to: Nicole van Der Wel, Meibergdreef 9, 1105AZ, Amsterdam, Netherlands. Email: n.n.vanderwel@amsterdamumc.nl.

Authorship note: MB, SVDN, EMB, and GB contributed equally to this work.

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

1Division of Rheumatology, Immunity and Inflammation, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

2Electron Microscopy Centre Amsterdam, Amsterdam University Medical Centre, Amsterdam, Netherlands.

3Host-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, London, United Kingdom.

4Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

5Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.

6Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James’s Hospital, Trinity College, Dublin, Ireland.

7Department of Chemical Biology, Stratingh Institute for Chemistry, Groningen, Netherlands.

8Casma Therapeutics, Cambridge, Massachusetts, USA.

Address correspondence to: D. Branch Moody, 60 Fenwood Road, Room 6006K, Boston, Massachusetts 02110, USA. Email: bmoody@bwh.harvard.edu. Or to: Maximiliano G Gutierrez, 1 Midland Road, London, NW1 1AT, United Kingdom. Email: max.g@crick.ac.uk. Or to: Nicole van Der Wel, Meibergdreef 9, 1105AZ, Amsterdam, Netherlands. Email: n.n.vanderwel@amsterdamumc.nl.

Authorship note: MB, SVDN, EMB, and GB contributed equally to this work.

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

1Division of Rheumatology, Immunity and Inflammation, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

2Electron Microscopy Centre Amsterdam, Amsterdam University Medical Centre, Amsterdam, Netherlands.

3Host-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, London, United Kingdom.

4Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

5Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.

6Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James’s Hospital, Trinity College, Dublin, Ireland.

7Department of Chemical Biology, Stratingh Institute for Chemistry, Groningen, Netherlands.

8Casma Therapeutics, Cambridge, Massachusetts, USA.

Address correspondence to: D. Branch Moody, 60 Fenwood Road, Room 6006K, Boston, Massachusetts 02110, USA. Email: bmoody@bwh.harvard.edu. Or to: Maximiliano G Gutierrez, 1 Midland Road, London, NW1 1AT, United Kingdom. Email: max.g@crick.ac.uk. Or to: Nicole van Der Wel, Meibergdreef 9, 1105AZ, Amsterdam, Netherlands. Email: n.n.vanderwel@amsterdamumc.nl.

Authorship note: MB, SVDN, EMB, and GB contributed equally to this work.

Find articles by Murphy, L. in: JCI | PubMed | Google Scholar

1Division of Rheumatology, Immunity and Inflammation, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

2Electron Microscopy Centre Amsterdam, Amsterdam University Medical Centre, Amsterdam, Netherlands.

3Host-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, London, United Kingdom.

4Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

5Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.

6Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James’s Hospital, Trinity College, Dublin, Ireland.

7Department of Chemical Biology, Stratingh Institute for Chemistry, Groningen, Netherlands.

8Casma Therapeutics, Cambridge, Massachusetts, USA.

Address correspondence to: D. Branch Moody, 60 Fenwood Road, Room 6006K, Boston, Massachusetts 02110, USA. Email: bmoody@bwh.harvard.edu. Or to: Maximiliano G Gutierrez, 1 Midland Road, London, NW1 1AT, United Kingdom. Email: max.g@crick.ac.uk. Or to: Nicole van Der Wel, Meibergdreef 9, 1105AZ, Amsterdam, Netherlands. Email: n.n.vanderwel@amsterdamumc.nl.

Authorship note: MB, SVDN, EMB, and GB contributed equally to this work.

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

1Division of Rheumatology, Immunity and Inflammation, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

2Electron Microscopy Centre Amsterdam, Amsterdam University Medical Centre, Amsterdam, Netherlands.

3Host-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, London, United Kingdom.

4Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

5Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.

6Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James’s Hospital, Trinity College, Dublin, Ireland.

7Department of Chemical Biology, Stratingh Institute for Chemistry, Groningen, Netherlands.

8Casma Therapeutics, Cambridge, Massachusetts, USA.

Address correspondence to: D. Branch Moody, 60 Fenwood Road, Room 6006K, Boston, Massachusetts 02110, USA. Email: bmoody@bwh.harvard.edu. Or to: Maximiliano G Gutierrez, 1 Midland Road, London, NW1 1AT, United Kingdom. Email: max.g@crick.ac.uk. Or to: Nicole van Der Wel, Meibergdreef 9, 1105AZ, Amsterdam, Netherlands. Email: n.n.vanderwel@amsterdamumc.nl.

Authorship note: MB, SVDN, EMB, and GB contributed equally to this work.

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

1Division of Rheumatology, Immunity and Inflammation, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

2Electron Microscopy Centre Amsterdam, Amsterdam University Medical Centre, Amsterdam, Netherlands.

3Host-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, London, United Kingdom.

4Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

5Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.

6Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James’s Hospital, Trinity College, Dublin, Ireland.

7Department of Chemical Biology, Stratingh Institute for Chemistry, Groningen, Netherlands.

8Casma Therapeutics, Cambridge, Massachusetts, USA.

Address correspondence to: D. Branch Moody, 60 Fenwood Road, Room 6006K, Boston, Massachusetts 02110, USA. Email: bmoody@bwh.harvard.edu. Or to: Maximiliano G Gutierrez, 1 Midland Road, London, NW1 1AT, United Kingdom. Email: max.g@crick.ac.uk. Or to: Nicole van Der Wel, Meibergdreef 9, 1105AZ, Amsterdam, Netherlands. Email: n.n.vanderwel@amsterdamumc.nl.

Authorship note: MB, SVDN, EMB, and GB contributed equally to this work.

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

1Division of Rheumatology, Immunity and Inflammation, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

2Electron Microscopy Centre Amsterdam, Amsterdam University Medical Centre, Amsterdam, Netherlands.

3Host-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, London, United Kingdom.

4Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

5Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.

6Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James’s Hospital, Trinity College, Dublin, Ireland.

7Department of Chemical Biology, Stratingh Institute for Chemistry, Groningen, Netherlands.

8Casma Therapeutics, Cambridge, Massachusetts, USA.

Address correspondence to: D. Branch Moody, 60 Fenwood Road, Room 6006K, Boston, Massachusetts 02110, USA. Email: bmoody@bwh.harvard.edu. Or to: Maximiliano G Gutierrez, 1 Midland Road, London, NW1 1AT, United Kingdom. Email: max.g@crick.ac.uk. Or to: Nicole van Der Wel, Meibergdreef 9, 1105AZ, Amsterdam, Netherlands. Email: n.n.vanderwel@amsterdamumc.nl.

Authorship note: MB, SVDN, EMB, and GB contributed equally to this work.

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

1Division of Rheumatology, Immunity and Inflammation, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

2Electron Microscopy Centre Amsterdam, Amsterdam University Medical Centre, Amsterdam, Netherlands.

3Host-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, London, United Kingdom.

4Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

5Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.

6Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James’s Hospital, Trinity College, Dublin, Ireland.

7Department of Chemical Biology, Stratingh Institute for Chemistry, Groningen, Netherlands.

8Casma Therapeutics, Cambridge, Massachusetts, USA.

Address correspondence to: D. Branch Moody, 60 Fenwood Road, Room 6006K, Boston, Massachusetts 02110, USA. Email: bmoody@bwh.harvard.edu. Or to: Maximiliano G Gutierrez, 1 Midland Road, London, NW1 1AT, United Kingdom. Email: max.g@crick.ac.uk. Or to: Nicole van Der Wel, Meibergdreef 9, 1105AZ, Amsterdam, Netherlands. Email: n.n.vanderwel@amsterdamumc.nl.

Authorship note: MB, SVDN, EMB, and GB contributed equally to this work.

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1Division of Rheumatology, Immunity and Inflammation, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

2Electron Microscopy Centre Amsterdam, Amsterdam University Medical Centre, Amsterdam, Netherlands.

3Host-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, London, United Kingdom.

4Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

5Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.

6Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James’s Hospital, Trinity College, Dublin, Ireland.

7Department of Chemical Biology, Stratingh Institute for Chemistry, Groningen, Netherlands.

8Casma Therapeutics, Cambridge, Massachusetts, USA.

Address correspondence to: D. Branch Moody, 60 Fenwood Road, Room 6006K, Boston, Massachusetts 02110, USA. Email: bmoody@bwh.harvard.edu. Or to: Maximiliano G Gutierrez, 1 Midland Road, London, NW1 1AT, United Kingdom. Email: max.g@crick.ac.uk. Or to: Nicole van Der Wel, Meibergdreef 9, 1105AZ, Amsterdam, Netherlands. Email: n.n.vanderwel@amsterdamumc.nl.

Authorship note: MB, SVDN, EMB, and GB contributed equally to this work.

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

Authorship note: MB, SVDN, EMB, and GB contributed equally to this work.

Published February 9, 2023 - More info

Published in Volume 133, Issue 6 on March 15, 2023
J Clin Invest. 2023;133(6):e161944. https://doi.org/10.1172/JCI161944.
© 2023 Bedard 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 February 9, 2023 - Version history
Received: May 31, 2022; Accepted: February 3, 2023 View PDF Related article:

Abstract

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), infects primarily macrophages, causing them to differentiate into lipid-laden foamy macrophages that are a primary source of tissue destruction in patients with TB. In this issue of the JCI, Bedard et al. demonstrate that 1-tuberculosinyladenosine, a virulence factor produced by M. tuberculosis, caused lysosomal dysfunction associated with lipid storage in the phagolysosome of macrophages in a manner that mimicked lysosomal storage diseases. This work sheds light on how M. tuberculosis manipulates host lipid metabolism for its survival and opens avenues toward host-directed therapy against TB.

Authors

Yoann Rombouts, Olivier Neyrolles

× Abstract

Induction of lipid-laden foamy macrophages is a cellular hallmark of tuberculosis (TB) disease, which involves the transformation of infected phagolysosomes from a site of killing into a nutrient-rich replicative niche. Here, we show that a terpenyl nucleoside shed from Mycobacterium tuberculosis, 1-tuberculosinyladenosine (1-TbAd), caused lysosomal maturation arrest and autophagy blockade, leading to lipid storage in M1 macrophages. Pure 1-TbAd, or infection with terpenyl nucleoside–producing M. tuberculosis, caused intralysosomal and peribacillary lipid storage patterns that matched both the molecules and subcellular locations known in foamy macrophages. Lipidomics showed that 1-TbAd induced storage of triacylglycerides and cholesterylesters and that 1-TbAd increased M. tuberculosis growth under conditions of restricted lipid access in macrophages. Furthermore, lipidomics identified 1-TbAd–induced lipid substrates that define Gaucher’s disease, Wolman’s disease, and other inborn lysosomal storage diseases. These data identify genetic and molecular causes of M. tuberculosis–induced lysosomal failure, leading to successful testing of an agonist of TRPML1 calcium channels that reverses lipid storage in cells. These data establish the host-directed cellular functions of an orphan effector molecule that promotes survival in macrophages, providing both an upstream cause and detailed picture of lysosome failure in foamy macrophages.

Graphical Abstract