TNF superfamily member 14 drives post-influenza depletion of alveolar macrophages, enabling secondary pneumococcal pneumonia
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
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
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Research Article Cell biology Infectious disease

TNF superfamily member 14 drives post-influenza depletion of alveolar macrophages, enabling secondary pneumococcal pneumonia

Abstract

Secondary bacterial infection, often caused by Streptococcus pneumoniae, is one of the most frequent and severe complications of influenza A virus–induced (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 S. pneumoniae 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 and S. pneumoniae coinfection. 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, whereas intrapulmonary transfer of genetically modified TR-AMs and antibody-mediated neutralization of specific pathway components alleviated disease severity. With mainly neutrophilic expression and high abundance in the bronchoalveolar fluid of patients with severe virus-induced acute respiratory distress syndrome, 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 the 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

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Figure 4

TNFSF14 treatment aggravates post-influenza TR-AM loss.

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TNFSF14 treatment aggravates post-influenza TR-AM loss. (A) Percentage o...
(A) Percentage of apoptotic cells within LTβR–TNFRSF14– and LTβR+ and/or TNFRSF14+ TR-AM subgroups on days 3 and 8 p.i. (n = 8–10 per group; data represent the mean ± SEM and were pooled from 2 independent experiments). (B and C) Cell survival proportional to light absorbance after a 24-hour treatment of murine (B) and human (C) TR-AMs with different doses of rTNFSF14 and normalized to control samples (n = 5–7; data represent the mean ± SEM and were pooled from 7 and 4 independent experiments in B and C, respectively). (D) Caspase 3/-7 activity after 24 hours of TR-AM treatment with 500 ng/mL rTNFSF14 (n = 6–7; data represent the mean ± SEM and were pooled from 6 independent experiments). (E) Schematics of rTNFSF14 application to IAV-infected mice on days 1 and 2 p.i., with analysis performed on day 3 p.i. Figure created with BioRender.com. (F) Percentage of live (annexin V– 7-AAD–) and apoptotic (annexin V+7-AAD–) TR-AMs (n = 3) on day 3 after rTNFSF14 treatment, data are representative of 3 different experiments. (G and H) Total BALF (n = 6–11, G) and lung-tissue TR-AMs (n = 7–10, H) on day 3 following rTNFSF14 treatment compared with mock infection. Data represent the mean ± SEM and were pooled from 7 independent experiments. *P < 0.05, ***P < 0.001, and ****P < 0.0001, by 1-way ANOVA with Tukey’s post hoc test (B, C, G, and H) and 2-way ANOVA with Tukey’s post hoc test (A, D, and F).