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ResearchIn-Press PreviewCell biologyInfectious disease Open Access | 10.1172/JCI185390

TNF Superfamily Member 14 Drives Post-Influenza Depletion of Alveolar Macrophages Enabling Secondary Pneumococcal Pneumonia

Christina Malainou,1 Christin Peteranderl,1 Maximiliano Ruben Ferrero,2 Ana Ivonne Vazquez-Armendariz,1 Ioannis Alexopoulos,1 Katharina Franz,1 Klara Knippenberg,1 Julian Better,1 Mohammad Estiri,1 Cheng-Yu Wu,3 Hendrik Schultheis,3 Judith Bushe,4 Maria-Luisa del Rio,5 Jose Ignacio Rodriguez-Barbosa,5 Klaus Pfeffer,6 Stefan Günther,3 Mario Looso,3 Achim Dieter Gruber,4 István Vadász,2 Ulrich Matt,1 and Susanne Herold1

1Department of Medicine V, Internal Medicine, Infectious Diseases and Infect, Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany

2Institute of Lung Health (ILH), Justus Liebig University Giessen, Giessen, Germany

3Excellence Cluster Cardio-Pulmonary Institute (CPI), Hessen, Germany

4Department of Veterinary Pathology, Free University Berlin, Berlin, Germany

5Transplantation Immunobiology Section, Institute of Molecular Biology, Genomics and Proteomics (INBIOMIC), University of León, León, Spain

6Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

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

1Department of Medicine V, Internal Medicine, Infectious Diseases and Infect, Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany

2Institute of Lung Health (ILH), Justus Liebig University Giessen, Giessen, Germany

3Excellence Cluster Cardio-Pulmonary Institute (CPI), Hessen, Germany

4Department of Veterinary Pathology, Free University Berlin, Berlin, Germany

5Transplantation Immunobiology Section, Institute of Molecular Biology, Genomics and Proteomics (INBIOMIC), University of León, León, Spain

6Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

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

1Department of Medicine V, Internal Medicine, Infectious Diseases and Infect, Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany

2Institute of Lung Health (ILH), Justus Liebig University Giessen, Giessen, Germany

3Excellence Cluster Cardio-Pulmonary Institute (CPI), Hessen, Germany

4Department of Veterinary Pathology, Free University Berlin, Berlin, Germany

5Transplantation Immunobiology Section, Institute of Molecular Biology, Genomics and Proteomics (INBIOMIC), University of León, León, Spain

6Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

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1Department of Medicine V, Internal Medicine, Infectious Diseases and Infect, Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany

2Institute of Lung Health (ILH), Justus Liebig University Giessen, Giessen, Germany

3Excellence Cluster Cardio-Pulmonary Institute (CPI), Hessen, Germany

4Department of Veterinary Pathology, Free University Berlin, Berlin, Germany

5Transplantation Immunobiology Section, Institute of Molecular Biology, Genomics and Proteomics (INBIOMIC), University of León, León, Spain

6Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

Find articles by Vazquez-Armendariz, A. in: PubMed | Google Scholar

1Department of Medicine V, Internal Medicine, Infectious Diseases and Infect, Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany

2Institute of Lung Health (ILH), Justus Liebig University Giessen, Giessen, Germany

3Excellence Cluster Cardio-Pulmonary Institute (CPI), Hessen, Germany

4Department of Veterinary Pathology, Free University Berlin, Berlin, Germany

5Transplantation Immunobiology Section, Institute of Molecular Biology, Genomics and Proteomics (INBIOMIC), University of León, León, Spain

6Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

Find articles by Alexopoulos, I. in: PubMed | Google Scholar

1Department of Medicine V, Internal Medicine, Infectious Diseases and Infect, Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany

2Institute of Lung Health (ILH), Justus Liebig University Giessen, Giessen, Germany

3Excellence Cluster Cardio-Pulmonary Institute (CPI), Hessen, Germany

4Department of Veterinary Pathology, Free University Berlin, Berlin, Germany

5Transplantation Immunobiology Section, Institute of Molecular Biology, Genomics and Proteomics (INBIOMIC), University of León, León, Spain

6Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

Find articles by Franz, K. in: PubMed | Google Scholar

1Department of Medicine V, Internal Medicine, Infectious Diseases and Infect, Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany

2Institute of Lung Health (ILH), Justus Liebig University Giessen, Giessen, Germany

3Excellence Cluster Cardio-Pulmonary Institute (CPI), Hessen, Germany

4Department of Veterinary Pathology, Free University Berlin, Berlin, Germany

5Transplantation Immunobiology Section, Institute of Molecular Biology, Genomics and Proteomics (INBIOMIC), University of León, León, Spain

6Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

Find articles by Knippenberg, K. in: PubMed | Google Scholar

1Department of Medicine V, Internal Medicine, Infectious Diseases and Infect, Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany

2Institute of Lung Health (ILH), Justus Liebig University Giessen, Giessen, Germany

3Excellence Cluster Cardio-Pulmonary Institute (CPI), Hessen, Germany

4Department of Veterinary Pathology, Free University Berlin, Berlin, Germany

5Transplantation Immunobiology Section, Institute of Molecular Biology, Genomics and Proteomics (INBIOMIC), University of León, León, Spain

6Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

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

1Department of Medicine V, Internal Medicine, Infectious Diseases and Infect, Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany

2Institute of Lung Health (ILH), Justus Liebig University Giessen, Giessen, Germany

3Excellence Cluster Cardio-Pulmonary Institute (CPI), Hessen, Germany

4Department of Veterinary Pathology, Free University Berlin, Berlin, Germany

5Transplantation Immunobiology Section, Institute of Molecular Biology, Genomics and Proteomics (INBIOMIC), University of León, León, Spain

6Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

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

1Department of Medicine V, Internal Medicine, Infectious Diseases and Infect, Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany

2Institute of Lung Health (ILH), Justus Liebig University Giessen, Giessen, Germany

3Excellence Cluster Cardio-Pulmonary Institute (CPI), Hessen, Germany

4Department of Veterinary Pathology, Free University Berlin, Berlin, Germany

5Transplantation Immunobiology Section, Institute of Molecular Biology, Genomics and Proteomics (INBIOMIC), University of León, León, Spain

6Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

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

1Department of Medicine V, Internal Medicine, Infectious Diseases and Infect, Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany

2Institute of Lung Health (ILH), Justus Liebig University Giessen, Giessen, Germany

3Excellence Cluster Cardio-Pulmonary Institute (CPI), Hessen, Germany

4Department of Veterinary Pathology, Free University Berlin, Berlin, Germany

5Transplantation Immunobiology Section, Institute of Molecular Biology, Genomics and Proteomics (INBIOMIC), University of León, León, Spain

6Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

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

1Department of Medicine V, Internal Medicine, Infectious Diseases and Infect, Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany

2Institute of Lung Health (ILH), Justus Liebig University Giessen, Giessen, Germany

3Excellence Cluster Cardio-Pulmonary Institute (CPI), Hessen, Germany

4Department of Veterinary Pathology, Free University Berlin, Berlin, Germany

5Transplantation Immunobiology Section, Institute of Molecular Biology, Genomics and Proteomics (INBIOMIC), University of León, León, Spain

6Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

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

1Department of Medicine V, Internal Medicine, Infectious Diseases and Infect, Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany

2Institute of Lung Health (ILH), Justus Liebig University Giessen, Giessen, Germany

3Excellence Cluster Cardio-Pulmonary Institute (CPI), Hessen, Germany

4Department of Veterinary Pathology, Free University Berlin, Berlin, Germany

5Transplantation Immunobiology Section, Institute of Molecular Biology, Genomics and Proteomics (INBIOMIC), University of León, León, Spain

6Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

Find articles by del Rio, M. in: PubMed | Google Scholar |

1Department of Medicine V, Internal Medicine, Infectious Diseases and Infect, Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany

2Institute of Lung Health (ILH), Justus Liebig University Giessen, Giessen, Germany

3Excellence Cluster Cardio-Pulmonary Institute (CPI), Hessen, Germany

4Department of Veterinary Pathology, Free University Berlin, Berlin, Germany

5Transplantation Immunobiology Section, Institute of Molecular Biology, Genomics and Proteomics (INBIOMIC), University of León, León, Spain

6Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

Find articles by Rodriguez-Barbosa, J. in: PubMed | Google Scholar |

1Department of Medicine V, Internal Medicine, Infectious Diseases and Infect, Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany

2Institute of Lung Health (ILH), Justus Liebig University Giessen, Giessen, Germany

3Excellence Cluster Cardio-Pulmonary Institute (CPI), Hessen, Germany

4Department of Veterinary Pathology, Free University Berlin, Berlin, Germany

5Transplantation Immunobiology Section, Institute of Molecular Biology, Genomics and Proteomics (INBIOMIC), University of León, León, Spain

6Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

Find articles by Pfeffer, K. in: PubMed | Google Scholar

1Department of Medicine V, Internal Medicine, Infectious Diseases and Infect, Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany

2Institute of Lung Health (ILH), Justus Liebig University Giessen, Giessen, Germany

3Excellence Cluster Cardio-Pulmonary Institute (CPI), Hessen, Germany

4Department of Veterinary Pathology, Free University Berlin, Berlin, Germany

5Transplantation Immunobiology Section, Institute of Molecular Biology, Genomics and Proteomics (INBIOMIC), University of León, León, Spain

6Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

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

1Department of Medicine V, Internal Medicine, Infectious Diseases and Infect, Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany

2Institute of Lung Health (ILH), Justus Liebig University Giessen, Giessen, Germany

3Excellence Cluster Cardio-Pulmonary Institute (CPI), Hessen, Germany

4Department of Veterinary Pathology, Free University Berlin, Berlin, Germany

5Transplantation Immunobiology Section, Institute of Molecular Biology, Genomics and Proteomics (INBIOMIC), University of León, León, Spain

6Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

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

1Department of Medicine V, Internal Medicine, Infectious Diseases and Infect, Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany

2Institute of Lung Health (ILH), Justus Liebig University Giessen, Giessen, Germany

3Excellence Cluster Cardio-Pulmonary Institute (CPI), Hessen, Germany

4Department of Veterinary Pathology, Free University Berlin, Berlin, Germany

5Transplantation Immunobiology Section, Institute of Molecular Biology, Genomics and Proteomics (INBIOMIC), University of León, León, Spain

6Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

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

1Department of Medicine V, Internal Medicine, Infectious Diseases and Infect, Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany

2Institute of Lung Health (ILH), Justus Liebig University Giessen, Giessen, Germany

3Excellence Cluster Cardio-Pulmonary Institute (CPI), Hessen, Germany

4Department of Veterinary Pathology, Free University Berlin, Berlin, Germany

5Transplantation Immunobiology Section, Institute of Molecular Biology, Genomics and Proteomics (INBIOMIC), University of León, León, Spain

6Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

Find articles by Vadász, I. in: PubMed | Google Scholar |

1Department of Medicine V, Internal Medicine, Infectious Diseases and Infect, Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany

2Institute of Lung Health (ILH), Justus Liebig University Giessen, Giessen, Germany

3Excellence Cluster Cardio-Pulmonary Institute (CPI), Hessen, Germany

4Department of Veterinary Pathology, Free University Berlin, Berlin, Germany

5Transplantation Immunobiology Section, Institute of Molecular Biology, Genomics and Proteomics (INBIOMIC), University of León, León, Spain

6Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

Find articles by Matt, U. in: PubMed | Google Scholar

1Department of Medicine V, Internal Medicine, Infectious Diseases and Infect, Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany

2Institute of Lung Health (ILH), Justus Liebig University Giessen, Giessen, Germany

3Excellence Cluster Cardio-Pulmonary Institute (CPI), Hessen, Germany

4Department of Veterinary Pathology, Free University Berlin, Berlin, Germany

5Transplantation Immunobiology Section, Institute of Molecular Biology, Genomics and Proteomics (INBIOMIC), University of León, León, Spain

6Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

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

Published November 18, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI185390.
Copyright © 2025, Malainou 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 November 18, 2025 - Version history
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Abstract

Secondary bacterial infection, often caused by Streptococcus pneumoniae (Spn), is one of the most frequent and severe complications of influenza A virus (IAV)-induced pneumonia. Phenotyping of the pulmonary immune cell landscape after IAV infection revealed a substantial depletion of the tissue-resident alveolar macrophage (TR-AM) population at day 7, which was associated with increased susceptibility to Spn outgrowth. To elucidate the molecular mechanisms underlying TR-AM depletion, and to define putative targets for treatment, we combined single-cell transcriptomics and cell-specific PCR profiling in an unbiased manner, using in vivo models of IAV infection and IAV/Spn co-infection. The TNF superfamily 14 (TNFSF14) ligand-receptor axis was revealed as the driving force behind post-influenza TR-AM death during the early infection phase, enabling the transition to pneumococcal pneumonia, while intrapulmonary transfer of genetically modified TR-AMs and antibody-mediated neutralization of specific pathway components alleviated disease severity. With a mainly neutrophilic expression and a high abundance in the bronchoalveolar fluid (BALF) of patients with severe virus-induced ARDS, TNFSF14 emerged as a key determinant of virus-driven lung injury. Targeting the TNFSF14-mediated intercellular communication network in the virus-infected lung can, therefore, improve host defense, minimizing the risk of subsequent bacterial pneumonia, and ameliorating disease outcome.

Supplemental material

View Unedited blot and gel images

View Transcriptomics data from cell death gene array for Tnfsf14-/- TR-AMs 0,3, and 7 days after IAV infection

View Transcriptomics data from cell death gene array for wt TR-AMs 0,3, and 7 days after IAV infection

View Transcriptomics data from TNFSF ligand and receptor gene array for wt TR-AMs 0,3, and 7 days after IAV infection

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Version history
  • Version 1 (November 18, 2025): In-Press Preview
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