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
View: Text | PDF
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

×

Figure 6

Neutrophils are the main cellular source of TNFSF14 during IAV infection.

Options: View larger image (or click on image) Download as PowerPoint
Neutrophils are the main cellular source of TNFSF14 during IAV infection...
(A) TNFSF14 expression on leukocytes, epithelial cells, endothelial cells, and MCs in the lungs of noninfected and day 7–infected mice (n = 4–5, were data pooled from 2 independent experiments). (B) TNFSF14 expression in different lung regions of mock- and IAV-infected WT mice on day 7 p.i. (n = 3–4; data are representative of 2 independent experiments). (C) Serum TNFSF14 levels on days 0, 3, and 7 p.i. (n = 3–5; data were pooled from 3 independent experiments). (D and E) Leukocyte scRNA-Seq analysis on day 3 p.i. (D) and day 7 p.i. (E) (n = 4; data are from 2 independent experiments). Monocyte and neutrophil clusters on day 3 p.i. were characterized according to the gene signature of the top 5 uniquely expressed genes per cluster. Dot plots depict Tnfsf14, Ltbr, and Tnfrsf14 expression. (F) qPCR analysis of Tnfsf14 expression in blood and BALF neutrophils (n = 4; data were pooled from 2 independent experiments). (G) qPCR analysisof TNFSF14 expression in BALF neutrophils from patients with severe IAV-induced ARDS compared with non-IAV controls (n = 3–4). (H) TNFSF14 expression on BALF leukocytes on day 3 p.i. and bone marrow–derived neubrophils (BM Neutrophils) from noninfected mice (n = 3–10; data were pooled from 2 independent experiments). (I and J) qPCR analysis in lung tissue (n = 7–9, I) and BALF ELISA (n = 9–13, J) for TNFSF14 expression on day 7 after neutrophil depletion. Data were pooled from 4 and 5 independent experiments, respectively. (K and L) BALF (K) and lung (L) TR-AMs on day 7 after neutrophil depletion (n = 8; data represent the mean ± SEM and were pooled from 4 and 5 independent experiments, respectively). *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by unpaired, 2-tailed Student’s t test (G and L), 1-way ANOVA with Tukey’s post hoc test (C, F, and H), and 2-way ANOVA with Tukey’s post hoc test (A and B).