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 7

Severity of post-influenza pneumococcal pneumonia is attenuated in the absence of TNFSF14.

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Severity of post-influenza pneumococcal pneumonia is attenuated in the a...
(A and B) Survival (A) and weight loss (B) after IAV and S. pneumoniae coinfection of WT and Tnfsf14–/– mice (n = 17–18; data represent the mean ± SEM and were pooled from 5 different experiments). (C and D) Bacterial burden in the BALF (C) and lungs (D) of WT and Tnfsf14–/– mice 9 days after IAV infection and 48 hours after S. pneumoniae infection (n = 10; data represent the mean ± SEM and were pooled from 8 independent experiments). (E) Total BALF TR-AM numbers for WT and Tnfsf14–/– mice 9 days after IAV and 48 hours after S. pneumoniae infection (n = 7–8; data represent the mean ± SEM and were pooled from 5 different experiments). (F and G) Survival (F) and weight loss (G) following IAV and S. pneumoniae coinfection and TNFSF14 blocking on day 2 p.i. (n = 12–16; data represent the mean ± SEM and were pooled from 5 independent experiments). (H) Schematics of the experimental layout for IAV and S. pneumoniae coinfection with adoptive transfer of naive WT, Tnfrsf14–/–, or Ltbr–/– TR-AMs on day 3 p.i. (I) Survival of WT mice upon IAV and S. pneumoniae coinfection and TR-AM adoptive transfer (n = 4–12; data represent the mean ± SEM and were pooled from 5 independent experiments). (J) Bacterial load in lysed WT and Ltbr–/– naive TR-AMs after ex vivo S. pneumoniae infection (n = 12; data represent the mean ± SEM and were pooled from 4 independent experiments). *P < 0.05 and **P < 0.01, by log-rank (Mantel-Cox) test (A, F, and I); unpaired, 2-tailed Student’s t test (B and G). Multiple unpaired Student’s t tests were performed for weight-loss comparisons at each time point after infection (C, D, E, and J). (K) Proposed hypothesis: Severe IAV–induced pneumonia is characterized by massive leukocyte recruitment, including neutrophils. Once in the alveoli, neutrophils start releasing TNFSF14, which is sensed by TR-AMs through ligation to the surface-expressed receptors TNFRSF14 and LTβR, culminating in TR-AM death, which increases host susceptibility to post-influenza pneumococcal pneumonia. Panels H and K were created with BioRender.com.