Clinical MedicineInfectious diseasePulmonology Open Access | 10.1172/jci.insight.173273

Hannah F. Schiff,1,2 Naomi F. Walker,3 Cesar Ugarte-Gil,4,5 Marc Tebruegge,6,7,8 Antigoni Manousopoulou,9 Spiros D. Garbis,1,9 Salah Mansour,1,2 Pak Ho (Michael) Wong,10 Gabrielle Rockett,10 Paolo Piazza,10 Mahesan Niranjan,2,11 Andres F. Vallejo,1 Christopher H. Woelk,12 Robert J. Wilkinson,13,14,15,16 Liku B. Tezera,1,2 Diana Garay-Baquero,1,2 and Paul Elkington1,2

1NIHR Biomedical Research Centre, School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.

2Institute for Life Sciences, Southampton, United Kingdom.

3Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.

4Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru.

5Department of Epidemiology, School of Public and Population Health, University of Texas Medical Branch, Galveston, Texas, USA.

6Department of Infection, Immunity & Inflammation, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.

7Department of Paediatrics, Klinik Ottakring, Wiener Gesundheitsverbund, Vienna, Austria.

8Department of Paediatrics, The University of Melbourne, Parkville, Australia.

9Proteas Bioanalytics, The Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, California, USA.

10Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

11Electronics and Computer Sciences, Faculty of Engineering and Physical Sciences, University of Southampton, Southampton, United Kingdom.

12Verge Genomics, South San Francisco, California, USA.

13Centre for Infectious Diseases Research in Africa, Institute of Infectious Diseases and Molecular Medicine, and

14Department of Medicine, University of Cape Town, Observatory, Republic of South Africa.

15Department of Infectious Diseases, Imperial College London, London, United Kingdom.

16The Francis Crick Institute, London, United Kingdom.

Address correspondence to: Paul Elkington, Clinical and Experimental Sciences, University of Southampton, Southampton SO16 1YD, United Kingdom. Phone: 00.44.23.8079.6671; Email: p.elkington@soton.ac.uk.

Authorship note: DGB and PE contributed equally to this work.

Find articles by Schiff, H. in: JCI | PubMed | Google Scholar |

1NIHR Biomedical Research Centre, School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.

2Institute for Life Sciences, Southampton, United Kingdom.

3Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.

4Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru.

5Department of Epidemiology, School of Public and Population Health, University of Texas Medical Branch, Galveston, Texas, USA.

6Department of Infection, Immunity & Inflammation, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.

7Department of Paediatrics, Klinik Ottakring, Wiener Gesundheitsverbund, Vienna, Austria.

8Department of Paediatrics, The University of Melbourne, Parkville, Australia.

9Proteas Bioanalytics, The Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, California, USA.

10Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

11Electronics and Computer Sciences, Faculty of Engineering and Physical Sciences, University of Southampton, Southampton, United Kingdom.

12Verge Genomics, South San Francisco, California, USA.

13Centre for Infectious Diseases Research in Africa, Institute of Infectious Diseases and Molecular Medicine, and

14Department of Medicine, University of Cape Town, Observatory, Republic of South Africa.

15Department of Infectious Diseases, Imperial College London, London, United Kingdom.

16The Francis Crick Institute, London, United Kingdom.

Address correspondence to: Paul Elkington, Clinical and Experimental Sciences, University of Southampton, Southampton SO16 1YD, United Kingdom. Phone: 00.44.23.8079.6671; Email: p.elkington@soton.ac.uk.

Authorship note: DGB and PE contributed equally to this work.

Find articles by Walker, N. in: JCI | PubMed | Google Scholar |

1NIHR Biomedical Research Centre, School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.

2Institute for Life Sciences, Southampton, United Kingdom.

3Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.

4Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru.

5Department of Epidemiology, School of Public and Population Health, University of Texas Medical Branch, Galveston, Texas, USA.

6Department of Infection, Immunity & Inflammation, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.

7Department of Paediatrics, Klinik Ottakring, Wiener Gesundheitsverbund, Vienna, Austria.

8Department of Paediatrics, The University of Melbourne, Parkville, Australia.

9Proteas Bioanalytics, The Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, California, USA.

10Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

11Electronics and Computer Sciences, Faculty of Engineering and Physical Sciences, University of Southampton, Southampton, United Kingdom.

12Verge Genomics, South San Francisco, California, USA.

13Centre for Infectious Diseases Research in Africa, Institute of Infectious Diseases and Molecular Medicine, and

14Department of Medicine, University of Cape Town, Observatory, Republic of South Africa.

15Department of Infectious Diseases, Imperial College London, London, United Kingdom.

16The Francis Crick Institute, London, United Kingdom.

Address correspondence to: Paul Elkington, Clinical and Experimental Sciences, University of Southampton, Southampton SO16 1YD, United Kingdom. Phone: 00.44.23.8079.6671; Email: p.elkington@soton.ac.uk.

Authorship note: DGB and PE contributed equally to this work.

Find articles by Ugarte-Gil, C. in: JCI | PubMed | Google Scholar |

1NIHR Biomedical Research Centre, School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.

2Institute for Life Sciences, Southampton, United Kingdom.

3Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.

4Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru.

5Department of Epidemiology, School of Public and Population Health, University of Texas Medical Branch, Galveston, Texas, USA.

6Department of Infection, Immunity & Inflammation, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.

7Department of Paediatrics, Klinik Ottakring, Wiener Gesundheitsverbund, Vienna, Austria.

8Department of Paediatrics, The University of Melbourne, Parkville, Australia.

9Proteas Bioanalytics, The Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, California, USA.

10Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

11Electronics and Computer Sciences, Faculty of Engineering and Physical Sciences, University of Southampton, Southampton, United Kingdom.

12Verge Genomics, South San Francisco, California, USA.

13Centre for Infectious Diseases Research in Africa, Institute of Infectious Diseases and Molecular Medicine, and

14Department of Medicine, University of Cape Town, Observatory, Republic of South Africa.

15Department of Infectious Diseases, Imperial College London, London, United Kingdom.

16The Francis Crick Institute, London, United Kingdom.

Address correspondence to: Paul Elkington, Clinical and Experimental Sciences, University of Southampton, Southampton SO16 1YD, United Kingdom. Phone: 00.44.23.8079.6671; Email: p.elkington@soton.ac.uk.

Authorship note: DGB and PE contributed equally to this work.

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

1NIHR Biomedical Research Centre, School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.

2Institute for Life Sciences, Southampton, United Kingdom.

3Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.

4Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru.

5Department of Epidemiology, School of Public and Population Health, University of Texas Medical Branch, Galveston, Texas, USA.

6Department of Infection, Immunity & Inflammation, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.

7Department of Paediatrics, Klinik Ottakring, Wiener Gesundheitsverbund, Vienna, Austria.

8Department of Paediatrics, The University of Melbourne, Parkville, Australia.

9Proteas Bioanalytics, The Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, California, USA.

10Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

11Electronics and Computer Sciences, Faculty of Engineering and Physical Sciences, University of Southampton, Southampton, United Kingdom.

12Verge Genomics, South San Francisco, California, USA.

13Centre for Infectious Diseases Research in Africa, Institute of Infectious Diseases and Molecular Medicine, and

14Department of Medicine, University of Cape Town, Observatory, Republic of South Africa.

15Department of Infectious Diseases, Imperial College London, London, United Kingdom.

16The Francis Crick Institute, London, United Kingdom.

Address correspondence to: Paul Elkington, Clinical and Experimental Sciences, University of Southampton, Southampton SO16 1YD, United Kingdom. Phone: 00.44.23.8079.6671; Email: p.elkington@soton.ac.uk.

Authorship note: DGB and PE contributed equally to this work.

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

1NIHR Biomedical Research Centre, School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.

2Institute for Life Sciences, Southampton, United Kingdom.

3Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.

4Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru.

5Department of Epidemiology, School of Public and Population Health, University of Texas Medical Branch, Galveston, Texas, USA.

6Department of Infection, Immunity & Inflammation, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.

7Department of Paediatrics, Klinik Ottakring, Wiener Gesundheitsverbund, Vienna, Austria.

8Department of Paediatrics, The University of Melbourne, Parkville, Australia.

9Proteas Bioanalytics, The Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, California, USA.

10Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

11Electronics and Computer Sciences, Faculty of Engineering and Physical Sciences, University of Southampton, Southampton, United Kingdom.

12Verge Genomics, South San Francisco, California, USA.

13Centre for Infectious Diseases Research in Africa, Institute of Infectious Diseases and Molecular Medicine, and

14Department of Medicine, University of Cape Town, Observatory, Republic of South Africa.

15Department of Infectious Diseases, Imperial College London, London, United Kingdom.

16The Francis Crick Institute, London, United Kingdom.

Address correspondence to: Paul Elkington, Clinical and Experimental Sciences, University of Southampton, Southampton SO16 1YD, United Kingdom. Phone: 00.44.23.8079.6671; Email: p.elkington@soton.ac.uk.

Authorship note: DGB and PE contributed equally to this work.

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

1NIHR Biomedical Research Centre, School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.

2Institute for Life Sciences, Southampton, United Kingdom.

3Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.

4Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru.

5Department of Epidemiology, School of Public and Population Health, University of Texas Medical Branch, Galveston, Texas, USA.

6Department of Infection, Immunity & Inflammation, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.

7Department of Paediatrics, Klinik Ottakring, Wiener Gesundheitsverbund, Vienna, Austria.

8Department of Paediatrics, The University of Melbourne, Parkville, Australia.

9Proteas Bioanalytics, The Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, California, USA.

10Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

11Electronics and Computer Sciences, Faculty of Engineering and Physical Sciences, University of Southampton, Southampton, United Kingdom.

12Verge Genomics, South San Francisco, California, USA.

13Centre for Infectious Diseases Research in Africa, Institute of Infectious Diseases and Molecular Medicine, and

14Department of Medicine, University of Cape Town, Observatory, Republic of South Africa.

15Department of Infectious Diseases, Imperial College London, London, United Kingdom.

16The Francis Crick Institute, London, United Kingdom.

Address correspondence to: Paul Elkington, Clinical and Experimental Sciences, University of Southampton, Southampton SO16 1YD, United Kingdom. Phone: 00.44.23.8079.6671; Email: p.elkington@soton.ac.uk.

Authorship note: DGB and PE contributed equally to this work.

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

1NIHR Biomedical Research Centre, School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.

2Institute for Life Sciences, Southampton, United Kingdom.

3Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.

4Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru.

5Department of Epidemiology, School of Public and Population Health, University of Texas Medical Branch, Galveston, Texas, USA.

6Department of Infection, Immunity & Inflammation, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.

7Department of Paediatrics, Klinik Ottakring, Wiener Gesundheitsverbund, Vienna, Austria.

8Department of Paediatrics, The University of Melbourne, Parkville, Australia.

9Proteas Bioanalytics, The Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, California, USA.

10Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

11Electronics and Computer Sciences, Faculty of Engineering and Physical Sciences, University of Southampton, Southampton, United Kingdom.

12Verge Genomics, South San Francisco, California, USA.

13Centre for Infectious Diseases Research in Africa, Institute of Infectious Diseases and Molecular Medicine, and

14Department of Medicine, University of Cape Town, Observatory, Republic of South Africa.

15Department of Infectious Diseases, Imperial College London, London, United Kingdom.

16The Francis Crick Institute, London, United Kingdom.

Address correspondence to: Paul Elkington, Clinical and Experimental Sciences, University of Southampton, Southampton SO16 1YD, United Kingdom. Phone: 00.44.23.8079.6671; Email: p.elkington@soton.ac.uk.

Authorship note: DGB and PE contributed equally to this work.

Find articles by Wong, P. in: JCI | PubMed | Google Scholar

1NIHR Biomedical Research Centre, School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.

2Institute for Life Sciences, Southampton, United Kingdom.

3Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.

4Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru.

5Department of Epidemiology, School of Public and Population Health, University of Texas Medical Branch, Galveston, Texas, USA.

6Department of Infection, Immunity & Inflammation, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.

7Department of Paediatrics, Klinik Ottakring, Wiener Gesundheitsverbund, Vienna, Austria.

8Department of Paediatrics, The University of Melbourne, Parkville, Australia.

9Proteas Bioanalytics, The Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, California, USA.

10Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

11Electronics and Computer Sciences, Faculty of Engineering and Physical Sciences, University of Southampton, Southampton, United Kingdom.

12Verge Genomics, South San Francisco, California, USA.

13Centre for Infectious Diseases Research in Africa, Institute of Infectious Diseases and Molecular Medicine, and

14Department of Medicine, University of Cape Town, Observatory, Republic of South Africa.

15Department of Infectious Diseases, Imperial College London, London, United Kingdom.

16The Francis Crick Institute, London, United Kingdom.

Address correspondence to: Paul Elkington, Clinical and Experimental Sciences, University of Southampton, Southampton SO16 1YD, United Kingdom. Phone: 00.44.23.8079.6671; Email: p.elkington@soton.ac.uk.

Authorship note: DGB and PE contributed equally to this work.

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

1NIHR Biomedical Research Centre, School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.

2Institute for Life Sciences, Southampton, United Kingdom.

3Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.

4Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru.

5Department of Epidemiology, School of Public and Population Health, University of Texas Medical Branch, Galveston, Texas, USA.

6Department of Infection, Immunity & Inflammation, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.

7Department of Paediatrics, Klinik Ottakring, Wiener Gesundheitsverbund, Vienna, Austria.

8Department of Paediatrics, The University of Melbourne, Parkville, Australia.

9Proteas Bioanalytics, The Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, California, USA.

10Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

11Electronics and Computer Sciences, Faculty of Engineering and Physical Sciences, University of Southampton, Southampton, United Kingdom.

12Verge Genomics, South San Francisco, California, USA.

13Centre for Infectious Diseases Research in Africa, Institute of Infectious Diseases and Molecular Medicine, and

14Department of Medicine, University of Cape Town, Observatory, Republic of South Africa.

15Department of Infectious Diseases, Imperial College London, London, United Kingdom.

16The Francis Crick Institute, London, United Kingdom.

Address correspondence to: Paul Elkington, Clinical and Experimental Sciences, University of Southampton, Southampton SO16 1YD, United Kingdom. Phone: 00.44.23.8079.6671; Email: p.elkington@soton.ac.uk.

Authorship note: DGB and PE contributed equally to this work.

Find articles by Piazza, P. in: JCI | PubMed | Google Scholar

1NIHR Biomedical Research Centre, School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.

2Institute for Life Sciences, Southampton, United Kingdom.

3Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.

4Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru.

5Department of Epidemiology, School of Public and Population Health, University of Texas Medical Branch, Galveston, Texas, USA.

6Department of Infection, Immunity & Inflammation, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.

7Department of Paediatrics, Klinik Ottakring, Wiener Gesundheitsverbund, Vienna, Austria.

8Department of Paediatrics, The University of Melbourne, Parkville, Australia.

9Proteas Bioanalytics, The Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, California, USA.

10Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

11Electronics and Computer Sciences, Faculty of Engineering and Physical Sciences, University of Southampton, Southampton, United Kingdom.

12Verge Genomics, South San Francisco, California, USA.

13Centre for Infectious Diseases Research in Africa, Institute of Infectious Diseases and Molecular Medicine, and

14Department of Medicine, University of Cape Town, Observatory, Republic of South Africa.

15Department of Infectious Diseases, Imperial College London, London, United Kingdom.

16The Francis Crick Institute, London, United Kingdom.

Address correspondence to: Paul Elkington, Clinical and Experimental Sciences, University of Southampton, Southampton SO16 1YD, United Kingdom. Phone: 00.44.23.8079.6671; Email: p.elkington@soton.ac.uk.

Authorship note: DGB and PE contributed equally to this work.

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

1NIHR Biomedical Research Centre, School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.

2Institute for Life Sciences, Southampton, United Kingdom.

3Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.

4Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru.

5Department of Epidemiology, School of Public and Population Health, University of Texas Medical Branch, Galveston, Texas, USA.

6Department of Infection, Immunity & Inflammation, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.

7Department of Paediatrics, Klinik Ottakring, Wiener Gesundheitsverbund, Vienna, Austria.

8Department of Paediatrics, The University of Melbourne, Parkville, Australia.

9Proteas Bioanalytics, The Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, California, USA.

10Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

11Electronics and Computer Sciences, Faculty of Engineering and Physical Sciences, University of Southampton, Southampton, United Kingdom.

12Verge Genomics, South San Francisco, California, USA.

13Centre for Infectious Diseases Research in Africa, Institute of Infectious Diseases and Molecular Medicine, and

14Department of Medicine, University of Cape Town, Observatory, Republic of South Africa.

15Department of Infectious Diseases, Imperial College London, London, United Kingdom.

16The Francis Crick Institute, London, United Kingdom.

Address correspondence to: Paul Elkington, Clinical and Experimental Sciences, University of Southampton, Southampton SO16 1YD, United Kingdom. Phone: 00.44.23.8079.6671; Email: p.elkington@soton.ac.uk.

Authorship note: DGB and PE contributed equally to this work.

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

1NIHR Biomedical Research Centre, School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.

2Institute for Life Sciences, Southampton, United Kingdom.

3Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.

4Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru.

5Department of Epidemiology, School of Public and Population Health, University of Texas Medical Branch, Galveston, Texas, USA.

6Department of Infection, Immunity & Inflammation, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.

7Department of Paediatrics, Klinik Ottakring, Wiener Gesundheitsverbund, Vienna, Austria.

8Department of Paediatrics, The University of Melbourne, Parkville, Australia.

9Proteas Bioanalytics, The Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, California, USA.

10Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

11Electronics and Computer Sciences, Faculty of Engineering and Physical Sciences, University of Southampton, Southampton, United Kingdom.

12Verge Genomics, South San Francisco, California, USA.

13Centre for Infectious Diseases Research in Africa, Institute of Infectious Diseases and Molecular Medicine, and

14Department of Medicine, University of Cape Town, Observatory, Republic of South Africa.

15Department of Infectious Diseases, Imperial College London, London, United Kingdom.

16The Francis Crick Institute, London, United Kingdom.

Address correspondence to: Paul Elkington, Clinical and Experimental Sciences, University of Southampton, Southampton SO16 1YD, United Kingdom. Phone: 00.44.23.8079.6671; Email: p.elkington@soton.ac.uk.

Authorship note: DGB and PE contributed equally to this work.

Find articles by Woelk, C. in: JCI | PubMed | Google Scholar

1NIHR Biomedical Research Centre, School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.

2Institute for Life Sciences, Southampton, United Kingdom.

3Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.

4Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru.

5Department of Epidemiology, School of Public and Population Health, University of Texas Medical Branch, Galveston, Texas, USA.

6Department of Infection, Immunity & Inflammation, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.

7Department of Paediatrics, Klinik Ottakring, Wiener Gesundheitsverbund, Vienna, Austria.

8Department of Paediatrics, The University of Melbourne, Parkville, Australia.

9Proteas Bioanalytics, The Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, California, USA.

10Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

11Electronics and Computer Sciences, Faculty of Engineering and Physical Sciences, University of Southampton, Southampton, United Kingdom.

12Verge Genomics, South San Francisco, California, USA.

13Centre for Infectious Diseases Research in Africa, Institute of Infectious Diseases and Molecular Medicine, and

14Department of Medicine, University of Cape Town, Observatory, Republic of South Africa.

15Department of Infectious Diseases, Imperial College London, London, United Kingdom.

16The Francis Crick Institute, London, United Kingdom.

Address correspondence to: Paul Elkington, Clinical and Experimental Sciences, University of Southampton, Southampton SO16 1YD, United Kingdom. Phone: 00.44.23.8079.6671; Email: p.elkington@soton.ac.uk.

Authorship note: DGB and PE contributed equally to this work.

Find articles by Wilkinson, R. in: JCI | PubMed | Google Scholar |

1NIHR Biomedical Research Centre, School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.

2Institute for Life Sciences, Southampton, United Kingdom.

3Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.

4Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru.

5Department of Epidemiology, School of Public and Population Health, University of Texas Medical Branch, Galveston, Texas, USA.

6Department of Infection, Immunity & Inflammation, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.

7Department of Paediatrics, Klinik Ottakring, Wiener Gesundheitsverbund, Vienna, Austria.

8Department of Paediatrics, The University of Melbourne, Parkville, Australia.

9Proteas Bioanalytics, The Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, California, USA.

10Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

11Electronics and Computer Sciences, Faculty of Engineering and Physical Sciences, University of Southampton, Southampton, United Kingdom.

12Verge Genomics, South San Francisco, California, USA.

13Centre for Infectious Diseases Research in Africa, Institute of Infectious Diseases and Molecular Medicine, and

14Department of Medicine, University of Cape Town, Observatory, Republic of South Africa.

15Department of Infectious Diseases, Imperial College London, London, United Kingdom.

16The Francis Crick Institute, London, United Kingdom.

Address correspondence to: Paul Elkington, Clinical and Experimental Sciences, University of Southampton, Southampton SO16 1YD, United Kingdom. Phone: 00.44.23.8079.6671; Email: p.elkington@soton.ac.uk.

Authorship note: DGB and PE contributed equally to this work.

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

1NIHR Biomedical Research Centre, School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.

2Institute for Life Sciences, Southampton, United Kingdom.

3Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.

4Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru.

5Department of Epidemiology, School of Public and Population Health, University of Texas Medical Branch, Galveston, Texas, USA.

6Department of Infection, Immunity & Inflammation, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.

7Department of Paediatrics, Klinik Ottakring, Wiener Gesundheitsverbund, Vienna, Austria.

8Department of Paediatrics, The University of Melbourne, Parkville, Australia.

9Proteas Bioanalytics, The Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, California, USA.

10Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

11Electronics and Computer Sciences, Faculty of Engineering and Physical Sciences, University of Southampton, Southampton, United Kingdom.

12Verge Genomics, South San Francisco, California, USA.

13Centre for Infectious Diseases Research in Africa, Institute of Infectious Diseases and Molecular Medicine, and

14Department of Medicine, University of Cape Town, Observatory, Republic of South Africa.

15Department of Infectious Diseases, Imperial College London, London, United Kingdom.

16The Francis Crick Institute, London, United Kingdom.

Address correspondence to: Paul Elkington, Clinical and Experimental Sciences, University of Southampton, Southampton SO16 1YD, United Kingdom. Phone: 00.44.23.8079.6671; Email: p.elkington@soton.ac.uk.

Authorship note: DGB and PE contributed equally to this work.

Find articles by Garay-Baquero, D. in: JCI | PubMed | Google Scholar |

1NIHR Biomedical Research Centre, School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.

2Institute for Life Sciences, Southampton, United Kingdom.

3Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.

4Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru.

5Department of Epidemiology, School of Public and Population Health, University of Texas Medical Branch, Galveston, Texas, USA.

6Department of Infection, Immunity & Inflammation, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.

7Department of Paediatrics, Klinik Ottakring, Wiener Gesundheitsverbund, Vienna, Austria.

8Department of Paediatrics, The University of Melbourne, Parkville, Australia.

9Proteas Bioanalytics, The Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, California, USA.

10Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

11Electronics and Computer Sciences, Faculty of Engineering and Physical Sciences, University of Southampton, Southampton, United Kingdom.

12Verge Genomics, South San Francisco, California, USA.

13Centre for Infectious Diseases Research in Africa, Institute of Infectious Diseases and Molecular Medicine, and

14Department of Medicine, University of Cape Town, Observatory, Republic of South Africa.

15Department of Infectious Diseases, Imperial College London, London, United Kingdom.

16The Francis Crick Institute, London, United Kingdom.

Address correspondence to: Paul Elkington, Clinical and Experimental Sciences, University of Southampton, Southampton SO16 1YD, United Kingdom. Phone: 00.44.23.8079.6671; Email: p.elkington@soton.ac.uk.

Authorship note: DGB and PE contributed equally to this work.

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Authorship note: DGB and PE contributed equally to this work.

Published March 21, 2024 - More info

Published in Volume 9, Issue 8 on April 22, 2024
JCI Insight. 2024;9(8):e173273. https://doi.org/10.1172/jci.insight.173273.
© 2024 Schiff 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 March 21, 2024 - Version history
Received: June 21, 2023; Accepted: March 13, 2024 View PDF Abstract

BACKGROUND. Novel biomarkers to identify infectious patients transmitting Mycobacterium tuberculosis are urgently needed to control the global tuberculosis (TB) pandemic. We hypothesized that proteins released into the plasma in active pulmonary TB are clinically useful biomarkers to distinguish TB cases from healthy individuals and patients with other respiratory infections.

METHODS. We applied a highly sensitive non-depletion tandem mass spectrometry discovery approach to investigate plasma protein expression in pulmonary TB cases compared to healthy controls in South African and Peruvian cohorts. Bioinformatic analysis using linear modeling and network correlation analyses identified 118 differentially expressed proteins, significant through 3 complementary analytical pipelines. Candidate biomarkers were subsequently analyzed in 2 validation cohorts of differing ethnicity using antibody-based proximity extension assays.

RESULTS. TB-specific host biomarkers were confirmed. A 6-protein diagnostic panel, comprising FETUB, FCGR3B, LRG1, SELL, CD14, and ADA2, differentiated patients with pulmonary TB from healthy controls and patients with other respiratory infections with high sensitivity and specificity in both cohorts.

CONCLUSION. This biomarker panel exceeds the World Health Organization Target Product Profile specificity criteria for a triage test for TB. The new biomarkers have potential for further development as near-patient TB screening assays, thereby helping to close the case-detection gap that fuels the global pandemic.

FUNDING. Medical Research Council (MRC) (MR/R001065/1, MR/S024220/1, MR/P023754/1, and MR/W025728/1); the MRC and the UK Foreign Commonwealth and Development Office; the UK National Institute for Health Research (NIHR); the Wellcome Trust (094000, 203135, and CC2112); Starter Grant for Clinical Lecturers (Academy of Medical Sciences UK); the British Infection Association; the Program for Advanced Research Capacities for AIDS in Peru at Universidad Peruana Cayetano Heredia (D43TW00976301) from the Fogarty International Center at the US NIH; the UK Technology Strategy Board/Innovate UK (101556); the Francis Crick Institute, which receives funding from UKRI-MRC (CC2112); Cancer Research UK (CC2112); and the NIHR Biomedical Research Centre of Imperial College NHS.

Graphical Abstract Introduction

Tuberculosis (TB) remains a disease of global significance, causing 1.3 million deaths and 10.6 million cases of active disease worldwide each year (1). Unfortunately, global control efforts have recently faltered due to the COVID-19 pandemic (2). The World Health Organization (WHO) has identified a global case detection gap of 4 million patients between the estimated incident