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The pathophysiology of sepsis and precision-medicine-based immunotherapy

Nature Immunology volume 25, pages 19–28 (2024)Cite this article

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Abstract

Sepsis remains a major cause of morbidity and mortality in both low- and high-income countries. Antibiotic therapy and supportive care have significantly improved survival following sepsis in the twentieth century, but further progress has been challenging. Immunotherapy trials for sepsis, mainly aimed at suppressing the immune response, from the 1990s and 2000s, have largely failed, in part owing to unresolved patient heterogeneity in the underlying immune disbalance. The past decade has brought the promise to break this blockade through technological developments based on omics-based technologies and systems medicine that can provide a much larger data space to describe in greater detail the immune endotypes in sepsis. Patient stratification opens new avenues towards precision medicine approaches that aim to apply immunotherapies to sepsis, on the basis of precise biomarkers and molecular mechanisms defining specific immune endotypes. This approach has the potential to lead to the establishment of immunotherapy as a successful pillar in the treatment of sepsis for future generations.

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Fig. 1: Immune responses in sepsis.
Fig. 2: Immune endotypes in sepsis.
Fig. 3: The steps towards immunotherapy in sepsis.

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Acknowledgements

The authors are partly supported by the ImmunoSep grant (no. 847422) and HDM-FUN grant from the Horizon 2020 program of the European Union. M.G.N. was partly supported by an ERC Advanced Grant (no. 833247) and a Spinoza Grant of the Netherlands Organization for Scientific Research. A.C.A., J.L.S. and M.G.N. are members of the excellence cluster ImmunoSensation (EXC 2151), funded by the German Research Foundation (DFG) under grant agreement no. 390873048. S.W. is currently funded by the Deutsche Forschungsgemeinschaft, DFG, project no. WE 4971/6-1, the Excellence Cluster Balance of the Microverse (EXC 2051; 390713860) and the Federal Ministry of Education and Research (BMBF) project no. 01EN2001.

Author information

Authors and Affiliations

  1. 4th Department of Internal Medicine, National and Kapodistrian University of Athens Medical School, Athens, Greece

    Evangelos J. Giamarellos-Bourboulis & Evdoxia Kyriazopoulou

  2. Hellenic Institute for the Study of Sepsis, Athens, Greece

    Evangelos J. Giamarellos-Bourboulis & Evdoxia Kyriazopoulou

  3. Systems Medicine, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany

    Anna C. Aschenbrenner & Joachim L. Schultze

  4. Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Friedrich-Schiller University, Jena, Germany

    Michael Bauer

  5. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria

    Christoph Bock

  6. Medical University of Vienna, Institute of Artificial Intelligence, Center for Medical Data Science, Vienna, Austria

    Christoph Bock

  7. Service of Immunology and Allergy and Center of Human Immunology Lausanne, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland

    Thierry Calandra

  8. The Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel

    Irit Gat-Viks

  9. Infectious Diseases Hospital, University of Medicine and Pharmacy ‘Iuliu Hatieganu’, Cluj-Napoca, Romania

    Mihaela Lupse

  10. Joint Research Unit HCL-bioMérieux, EA 7426 ‘Pathophysiology of Injury-Induced Immunosuppression’ (Université Claude Bernard Lyon 1 – Hospices Civils de Lyon, bioMérieux), Lyon, France

    Guillaume Monneret

  11. Immunology Laboratory, Edouard Herriot Hospital – Hospices Civils de Lyon, Lyon, France

    Guillaume Monneret

  12. Department of Intensive Care, Radboud University Medical Center, Nijmegen, The Netherlands

    Peter Pickkers

  13. Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands

    Peter Pickkers, Frank L. van de Veerdonk & Mihai G. Netea

  14. PRECISE Platform for Single Cell Genomics and Epigenomics, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) and the University of Bonn, Bonn, Germany

    Joachim L. Schultze

  15. Genomics and Immunoregulation, Life & Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany

    Joachim L. Schultze & Mihai G. Netea

  16. Division of Infectious Diseases, Amsterdam University Medical Centers (Amsterdam UMC), Center for Experimental and Molecular Medicine (CEMM), University of Amsterdam, Amsterdam, The Netherlands

    Tom van der Poll & W. Joost Wiersinga

  17. Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands

    Frank L. van de Veerdonk & Mihai G. Netea

  18. Department of Intensive Care and Laboratory of Experimental Intensive Care and Anesthesiology L.E.C.A. Amsterdam Medical Centers, University of Amsterdam, Amsterdam, The Netherlands

    Alexander P. J. Vlaar

  19. Institute for Infectious Disease and Infection Control, Jena University Hospital, Friedrich-Schiller University, Jena, Germany

    Sebastian Weis

  20. Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute-HKI, Jena, Germany

    Sebastian Weis

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  1. Evangelos J. Giamarellos-Bourboulis
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Contributions

E.J.G.-B., M.B., C.B., T.C., I.G.-V., E.K., M.L., G.M., J.L.S., A.C.A., T.v.d.P, P.P., F.L.v.d.V., A.P.J.V., S.W., W.J.W., M.G.N. designed the manuscript, wrote the manuscript and corrected subsequent versions.

Corresponding author

Correspondence to Mihai G. Netea.

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Competing interests

E.J.G.-B. has received honoraria from Abbott, bioMérieux, Brahms, GSK, InflaRx, Sobi and XBiotech, and independent educational grants from Abbott, AxisShield, bioMérieux, InflaRx, Johnson & Johnson, MSD, Sobi and XBiotech. A.V. receives consulting fees from Inflarx paid to Amsterdam UMC. M.B. is cofounder and holds shares of SmartDyeLivery, Jena. M.G.N. is a scientific founder and holds shares of TTxD, BioTRIP and Lemba. All other authors have no conflicts of interest.

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Nature Immunology thanks the anonymous reviewers for their contribution to the peer review of this work. Primary Handling Editor: Jamie D. K. Wilson, in collaboration with the Nature Immunology team.

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Supplementary Table 1

Supplementary Table 1

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Giamarellos-Bourboulis, E.J., Aschenbrenner, A.C., Bauer, M. et al. The pathophysiology of sepsis and precision-medicine-based immunotherapy. Nat Immunol 25, 19–28 (2024). https://doi.org/10.1038/s41590-023-01660-5

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