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Unique human immune signature of Ebola virus disease in Guinea

Nature volume 533, pages 100104 (05 May 2016) | Download Citation

Abstract

Despite the magnitude of the Ebola virus disease (EVD) outbreak in West Africa, there is still a fundamental lack of knowledge about the pathophysiology of EVD1. In particular, very little is known about human immune responses to Ebola virus2,3. Here we evaluate the physiology of the human T cell immune response in EVD patients at the time of admission to the Ebola Treatment Center in Guinea, and longitudinally until discharge or death. Through the use of multiparametric flow cytometry established by the European Mobile Laboratory in the field, we identify an immune signature that is unique in EVD fatalities. Fatal EVD was characterized by a high percentage of CD4+ and CD8+ T cells expressing the inhibitory molecules CTLA-4 and PD-1, which correlated with elevated inflammatory markers and high virus load. Conversely, surviving individuals showed significantly lower expression of CTLA-4 and PD-1 as well as lower inflammation, despite comparable overall T cell activation. Concomitant with virus clearance, survivors mounted a robust Ebola-virus-specific T cell response. Our findings suggest that dysregulation of the T cell response is a key component of EVD pathophysiology.

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Acknowledgements

We thank the African Union, MSF and WHO field teams and the Guinean health authorities in Guéckédou, Coyah and Conakry for their commitment and cooperation. We also thank J. Snyder-Cappione (Boston University) and M. Altfeld (Heinrich Pette Institute) for technical support. The EMLab is a technical partner of the WHO Emerging and Dangerous Pathogens Laboratory Network (EDPLN), and the Global Outbreak Alert and Response Network (GOARN) and the deployments in West Africa have been coordinated and supported by the GOARN Operational Support Team at WHO/HQ. This work was carried out in the context of the project EVIDENT (Ebola virus disease: correlates of protection, determinants of outcome, and clinical management) that received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 666100 and in the context of service contract IFS/2011/272-372 funded by Directorate-General for International Cooperation and Development. The project was further supported by grant GU 883/4-1 from the German Research Foundation. This project has been funded in in part with funds from the Spanish National Plan for Research and Development ISCIII and FEDER RD12/0018/006 as well as federal funds from the Frederick National Laboratory for Cancer Research, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This research was supported in part by the Intramural Research Program of the NIH, Frederick National Laboratory, Center for Cancer Research. A.L. is a recipient of a pre-doctoral fellowship from the Leibniz Center of Infection. Z.K. is a recipient of a fellowship from the European Program for Public Health Microbiology Training (EUPHEM).

Author information

Author notes

    • Paula Ruibal
    • , Lisa Oestereich
    • , Anja Lüdtke
    •  & Beate Becker-Ziaja

    These authors contributed equally to this work.

    • Stephan Günther
    •  & César Muñoz-Fontela

    These authors jointly supervised this work.

Affiliations

  1. Heinrich Pette Institute, Leibniz Institute for Experimental Virology, 20251 Hamburg, Germany

    • Paula Ruibal
    • , Anja Lüdtke
    • , Eva Herker
    •  & César Muñoz-Fontela
  2. Bernhard Nocht Institute for Tropical Medicine, World Health Organization Collaborating Center for Arbovirus and Hemorrhagic Fever Reference and Research, 20359 Hamburg, Germany

    • Paula Ruibal
    • , Lisa Oestereich
    • , Anja Lüdtke
    • , Beate Becker-Ziaja
    • , David M. Wozniak
    • , Romy Kerber
    • , Mar Cabeza-Cabrerizo
    • , Sophie Duraffour
    • , Elisa Pallasch
    • , Tobias Holm
    • , Thomas Jacobs
    • , Benno Kreuels
    • , Martin Gabriel
    • , Stephan Günther
    •  & César Muñoz-Fontela
  3. German Center for Infection Research (DZIF), Partner Sites Hamburg, Munich, and Marburg, Germany

    • Paula Ruibal
    • , Lisa Oestereich
    • , Anja Lüdtke
    • , Beate Becker-Ziaja
    • , David M. Wozniak
    • , Romy Kerber
    • , Elisa Pallasch
    • , Katja Nitzsche
    • , Tobias Holm
    • , Roman Wölfel
    • , Kilian Stoecker
    • , Erna Fleischmann
    • , Thomas Strecker
    • , Anne Kelterbaum
    • , Peter Molkenthin
    • , Svenja Wolff
    • , Gordian Schudt
    • , Benno Kreuels
    • , Dominic Wichmann
    • , Marylyn M. Addo
    • , Ansgar W. Lohse
    • , Martin Gabriel
    • , Stephan Günther
    •  & César Muñoz-Fontela
  4. European Mobile Laboratory Consortium, Bernhard-Nocht-Institute for Tropical Medicine, D-20359 Hamburg, Germany

    • Paula Ruibal
    • , Lisa Oestereich
    • , Anja Lüdtke
    • , Beate Becker-Ziaja
    • , David M. Wozniak
    • , Romy Kerber
    • , Miša Korva
    • , Mar Cabeza-Cabrerizo
    • , Joseph A. Bore
    • , Fara Raymond Koundouno
    • , Sophie Duraffour
    • , Romy Weller
    • , Anja Thorenz
    • , Eleonora Cimini
    • , Domenico Viola
    • , Chiara Agrati
    • , Johanna Repits
    • , Babak Afrough
    • , Lauren A. Cowley
    • , Didier Ngabo
    • , Julia Hinzmann
    • , Marc Mertens
    • , Inês Vitoriano
    • , Christopher H. Logue
    • , Jan Peter Boettcher
    • , Elisa Pallasch
    • , Andreas Sachse
    • , Amadou Bah
    • , Katja Nitzsche
    • , Eeva Kuisma
    • , Janine Michel
    • , Tobias Holm
    • , Elsa-Gayle Zekeng
    • , Isabel García-Dorival
    • , Roman Wölfel
    • , Kilian Stoecker
    • , Erna Fleischmann
    • , Thomas Strecker
    • , Antonino Di Caro
    • , Tatjana Avšič-Županc
    • , Andreas Kurth
    • , Silvia Meschi
    • , Stephane Mély
    • , Edmund Newman
    • , Anne Bocquin
    • , Zoltan Kis
    • , Anne Kelterbaum
    • , Peter Molkenthin
    • , Fabrizio Carletti
    • , Jasmine Portmann
    • , Svenja Wolff
    • , Concetta Castilletti
    • , Gordian Schudt
    • , Alexandra Fizet
    • , Lisa J. Ottowell
    • , Martin Gabriel
    • , Miles W. Carroll
    • , Stephan Günther
    •  & César Muñoz-Fontela
  5. Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia

    • Miša Korva
    •  & Tatjana Avšič-Županc
  6. Institute of Experimental Virology, Twincore, Center for Experimental and Clinical Infection Research, 30625 Hannover, Germany

    • Romy Weller
  7. Hannover Medical School, 30625 Hannover, Germany

    • Anja Thorenz
  8. National Institute for Infectious Diseases ‘Lazzaro Spallanzani’, 00149 Rome, Italy

    • Eleonora Cimini
    • , Domenico Viola
    • , Chiara Agrati
    • , Antonino Di Caro
    • , Silvia Meschi
    • , Fabrizio Carletti
    •  & Concetta Castilletti
  9. Public Health England, Porton Down, Salisbury SP4 0JG, UK

    • Babak Afrough
    • , Didier Ngabo
    • , Inês Vitoriano
    • , Christopher H. Logue
    • , Eeva Kuisma
    • , Edmund Newman
    • , Lisa J. Ottowell
    •  & Miles W. Carroll
  10. Public Health England, Colindale Ave, London NW9 5EQ, UK

    • Lauren A. Cowley
  11. Robert Koch Institute, 13353 Berlin, Germany

    • Julia Hinzmann
    • , Jan Peter Boettcher
    • , Andreas Sachse
    • , Janine Michel
    • , Andreas Kurth
    •  & Nobila Ouedraogo
  12. Friedrich Loeffler Institute, 17493 Greifswald-Island of Riems, Germany

    • Marc Mertens
  13. Swiss Tropical and Public Health Institute, 4051 Basel, Switzerland

    • Amadou Bah
  14. Institute of Infection and Global Health, University of Liverpool, Liverpool L69 7BE, UK

    • Isabel García-Dorival
  15. Bundeswehr Institute of Microbiology, 80937 Munich, Germany

    • Roman Wölfel
    • , Kilian Stoecker
    • , Erna Fleischmann
    •  & Peter Molkenthin
  16. Institute of Virology, Philipps University, 35043 Marburg, Germany

    • Thomas Strecker
    • , Anne Kelterbaum
    • , Svenja Wolff
    •  & Gordian Schudt
  17. Laboratoire P4-Jean Mérieux, US003 INSERM, 69365 Lyon, France

    • Stephane Mély
    •  & Anne Bocquin
  18. National Center for Epidemiology, Hungarian National Biosafety Laboratory, H1097 Budapest, Hungary

    • Zoltan Kis
  19. European Centre for Disease Prevention and Control, 171 65 Solna, Sweden

    • Zoltan Kis
    •  & Ettore Severi
  20. Federal Office for Civil Protection, CH-3700 Spiez, Switzerland

    • Jasmine Portmann
  21. Unité de Biologie des Infections Virales Emergentes, Institut Pasteur, 69365 Lyon, France

    • Alexandra Fizet
  22. Eurice, European Research and Project Office, 10115 Berlin, Germany

    • Birte Kretschmer
  23. Infectious Diseases Unit, Internal Medicine Service, Hospital La Paz, 28046 Madrid, Spain

    • Mar Lago
  24. National Center of Microbiology, Institute of Health ‘Carlos III’, 28220 Madrid, Spain

    • Anabel Negredo
    • , Leticia Franco
    •  & Pedro Anda
  25. University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany

    • Stefan Schmiedel
    • , Benno Kreuels
    • , Dominic Wichmann
    • , Marylyn M. Addo
    •  & Ansgar W. Lohse
  26. Médecins sans Frontières, B-1050 Brussels, Belgium

    • Hilde De Clerck
    • , Carolina Nanclares
    • , Sylvie Jonckheere
    • , Michel Van Herp
    •  & Armand Sprecher
  27. Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA

    • Gao Xiaojiang
    •  & Mary Carrington
  28. Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts 02139, USA

    • Gao Xiaojiang
    •  & Mary Carrington
  29. Hospital Militar Central Dr. Carlos J. Finlay, 11400 Havana, Cuba

    • Osvaldo Miranda
    •  & Carlos M. Castro
  30. World Health Organization, 1211 Geneva 27, Switzerland

    • Patrick Drury
    • , Pierre Formenty
    •  & Boubacar Diallo
  31. Institut National de Santé Publique, 2101 Conakry, Guinea

    • Lamine Koivogui
  32. Université Gamal Abdel Nasser de Conakry, CHU Donka, 2101 Conakry, Guinea

    • N’Faly Magassouba

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Contributions

P.R., L.O., A.L. and B.B.-Z. performed all the experiments of this study and contributed equally. Authors affiliated with the Cuban medical teams, Médecins sans Frontières, Infectious Diseases Unit, Internal Medicine Service, Hospital La Paz, and the University Medical Center Hamburg-Eppendorf treated all the patients in this study and provided samples. All authors affiliated with the European Mobile Laboratory Consortium performed EVD diagnostics, collected samples in the field and/or coordinated EMLab operations and sample shipment to Conakry and Hamburg. Authors affiliated with WHO provided the logistics necessary to perform this study. A.S., E.S., P.F., N.O. and B.D. provided patient outcome, epidemiology and demographic data. E.H. and T.J. provided support for data analysis. B.K. provided logistic support for the EVIDENT project teams. G.X. and M.C. performed HLA typing. S.G. coordinated the study. C.M.-F. designed the study, performed experiments and wrote the manuscript with S.G. All authors discussed the results and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Stephan Günther or César Muñoz-Fontela.

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DOI

https://doi.org/10.1038/nature17949

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