Abstract
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.
Highlights
Influenza viruses (IV) may cause primary viral pneumonia in humans with rapid progression to lung failure and fatal outcome, and treatment options for this sometimes devastating disease are limited [1, 2]
We demonstrate that highly pathogenic Influenza Virus (IV) infect cells of the epithelial stem/progenitor cell niche, which significantly impairs repair processes within the damaged lung, as demonstrated by transplantation experiments using intrapulmonary delivery of infected versus non-infected stem cells into IV-injured mice
Analyses of the underlying virus-host interactions reveal that IV infection of epithelial stem/progenitor cells results in blockade of a pathway involving Wnt/β-catenin and fibroblast growth factor receptor 2b (Fgfr2b) activation within a regenerative epithelial-mesenchymal cell signaling network
Summary
Influenza viruses (IV) may cause primary viral pneumonia in humans with rapid progression to lung failure and fatal outcome, and treatment options for this sometimes devastating disease are limited [1, 2]. Histopathology and clinical features of IV-induced lung injury in humans resemble those of other forms of ARDS (acute respiratory distress syndrome) and are characterized by apoptotic and necrotic airway and alveolar epithelial cell death, loss of pulmonary barrier function and severe hypoxemia [1, 3, 4]. IV primarily infect cell subsets of the upper and lower respiratory tract. In the latter, these are ciliated and goblet cells, club cells and alveolar epithelial cells type II (AECII) [5,6,7]. The cellular communication patterns and molecular networks underlying regeneration of the distal lung compartment after severe pathogen-associated injury are incompletely understood to date. The distinct mechanisms of interaction between injury-causing pathogens with components of regenerative signaling pathways within the lung stem cell niche, determining outcome of the repair response, have not been studied in detail
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