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

[EN] 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...

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Detalles Bibliográficos
Autores: Malainou, Christina, Peteranderl, Christin, Ferrero, Maximiliano Ruben, Vázquez Armendariz, Ana Ivonne, Alexopoulos, Ioannis, Franz, Katharina, Knippenberg, Klara, Better, Julian, Estiri, Mohammad, Wu, Cheng-Yu, Schultheis, Hendrik, Bushe, Judith, Río González, María Luisa del, Rodríguez Barbosa, José Ignacio, Pfeffer, Klaus, Günther, Stefan, Looso, Mario, Gruber, Achim Dieter, Vadász, István, Matt, Ulrich, Herold, Susanne
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2025
País:España
Institución:Universidad de León
Repositorio:BULERIA. Repositorio Institucional de la Universidad de León
OAI Identifier:oai:buleria.unileon.es:10612/26494
Acceso en línea:https://www.jci.org/articles/view/185390
https://hdl.handle.net/10612/26494
https://doi.org/10.1172/JCI185390
Access Level:acceso abierto
Palabra clave:Inmunología
Influenza A virus
Pneumonia
Alveolar macrophages
TNF superfamily
Streptococcus pneumoniae
2412 Inmunología
Descripción
Sumario:[EN] 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

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