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

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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.

Authors

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