Influenza Virus Infects Epithelial Stem/Progenitor Cells of the Distal Lung: Impact on Fgfr2b-Driven Epithelial Repair.
Influenza Virus (IV) pneumonia is associated with severe damage of the lung epithelium and respiratory failure. Apart from efficient host defense, structural repair of the injured epithelium is crucial for survival of severe pneumonia. The molecular mechanisms underlying stem/progenitor cell mediated regenerative responses are not well characterized. In particular, the impact of IV infection on lung stem cells and their regenerative responses remains elusive. Our study demonstrates that a highly pathogenic IV infects various cell populations in the murine lung, but displays a strong tropism to an epithelial cell subset with high proliferative capacity, defined by the signature EpCamhighCD24lowintegrin(α6)high. This cell fraction expressed the stem cell antigen-1, highly enriched lung stem/progenitor cells previously characterized by the signature integrin(β4)+CD200+, and upregulated the p63/krt5 regeneration program after IV-induced injury. Using 3-dimensional organoid cultures derived from these epithelial stem/progenitor cells (EpiSPC), and in vivo infection models including transgenic mice, we reveal that their expansion, barrier renewal and outcome after IV-induced injury critically depended on Fgfr2b signaling. Importantly, IV infected EpiSPC exhibited severely impaired renewal capacity due to IV-induced blockade of β-catenin-dependent Fgfr2b signaling, evidenced by loss of alveolar tissue repair capacity after intrapulmonary EpiSPC transplantation in vivo. Intratracheal application of exogenous Fgf10, however, resulted in increased engagement of non-infected EpiSPC for tissue regeneration, demonstrated by improved proliferative potential, restoration of alveolar barrier function and increased survival following IV pneumonia. Together, these data suggest that tropism of IV to distal lung stem cell niches represents an important factor of pathogenicity and highlight impaired Fgfr2b signaling as underlying mechanism. Furthermore, increase of alveolar Fgf10 levels may represent a putative therapy to overcome regeneration failure after IV-induced lung injury.
Department of Internal Medicine II, Universities Giessen & Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Giessen, Germany.
Jennifer
J
Quantius
Department of Internal Medicine II, Universities Giessen & Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Giessen, Germany.
Carole
C
Schmoldt
Department of Internal Medicine II, Universities Giessen & Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Giessen, Germany.
Ana I
AI
Vazquez-Armendariz
Department of Internal Medicine II, Universities Giessen & Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Giessen, Germany.
Christin
C
Becker
Excellence Cluster Cardio-Pulmonary System (ECCPS), Universities Giessen & Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Giessen, Germany.
Elie
E
El Agha
Excellence Cluster Cardio-Pulmonary System (ECCPS), Universities Giessen & Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Giessen, Germany.|Department of Pathology, Justus-Liebig-University Giessen, Giessen, Germany.
Jochen
J
Wilhelm
Excellence Cluster Cardio-Pulmonary System (ECCPS), Universities Giessen & Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Giessen, Germany.
Rory E
RE
Morty
Department of Internal Medicine II, Universities Giessen & Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Giessen, Germany.|Excellence Cluster Cardio-Pulmonary System (ECCPS), Universities Giessen & Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Giessen, Germany.
István
I
Vadász
Department of Internal Medicine II, Universities Giessen & Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Giessen, Germany.|Excellence Cluster Cardio-Pulmonary System (ECCPS), Universities Giessen & Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Giessen, Germany.
Konstantin
K
Mayer
Department of Pathology, Justus-Liebig-University Giessen, Giessen, Germany.
Stefan
S
Gattenloehner
Institute of Pathology and Cytology, Wetzlar, Germany, member of the German Center for Lung Research (DZL), Giessen, Germany.
Ludger
L
Fink
Institute of Virology, Philipps University, Marburg, Germany.
Mikhail
M
Matrosovich
College of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Xiaokun
X
Li
Department of Internal Medicine II, Universities Giessen & Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Giessen, Germany.|Excellence Cluster Cardio-Pulmonary System (ECCPS), Universities Giessen & Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Giessen, Germany.|Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
Werner
W
Seeger
Department of Internal Medicine II, Universities Giessen & Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Giessen, Germany.|Excellence Cluster Cardio-Pulmonary System (ECCPS), Universities Giessen & Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Giessen, Germany.
Juergen
J
Lohmeyer
Excellence Cluster Cardio-Pulmonary System (ECCPS), Universities Giessen & Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Giessen, Germany.|College of life and Environmental sciences and College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou University town, Zhejiang, China.
Saverio
S
Bellusci
Department of Internal Medicine II, Universities Giessen & Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Giessen, Germany.|Excellence Cluster Cardio-Pulmonary System (ECCPS), Universities Giessen & Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Giessen, Germany.
Susanne
S
Herold
D000818:Animals; D002469:Cell Separation; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D009980:Influenza A virus / Q000472:pathogenicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009976:Orthomyxoviridae Infections / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D011024:Pneumonia, Viral / Q000378:metabolism / Q000473:pathology / Q000821:virology; D060888:Real-Time Polymerase Chain Reaction; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism / Q000821:virology*
D051497:Receptor, Fibroblast Growth Factor, Type 2