Impact of virus and host factors on lung epithelial cell injury and repair in severe influenza virus pneumonia

Research areas: Pneumology, Infectious Diseases, Cell Biology, Molecular Virology

Viral pneumonia is characterized by extensive lung injury, usually followed by stem cell-mediated epithelial repair. We recently defined a pool of bronchoalveolar stem cells (BASC) that repair both bronchial and alveolar tissue after IAV-induced injury. Using transgenic in vivo mouse and bronchoalveolar lung organoid (BALO) infection models, as well as first-in-man approaches such as inhalative granulocyte/macrophage colony-stimulating factor (GM-CSF) in patients with severe virus-induced lung injury, we revealed that BASC´s and alveolar epithelial cells type II´s regenerative responses depend on cooperation with district mesenchymal cells of the stem cell niche and on GM‑CSF release upon IAV infection.

Therefore, our main aims are to identify the host signaling pathways at the virus-host interface that drive alveolar epithelial cell injury and foster repair from distinct lung stem cell niches, and to elucidate how viral pathogenicity factors impact on these mechanisms, resulting in aggravated damage of the distal lung epithelium and in impaired or aberrant repair after virus-induced pneumonia.

Project-related publications of the investigator:

  • Vazquez-Armendariz AI, Herold S. 2021. From Clones to Buds and Branches: The Use of Lung Organoids to Model Branching Morphogenesis Ex Vivo. Front Cell Dev Biol 9:631579.
  • Vazquez-Armendariz AI, Heiner M, El Agha E, Salwig I, Hoek A, Hessler MC, Shalashova I, Shrestha A, Carraro G, Mengel JP, Gunther A, Morty RE, Vadasz I, Schwemmle M, Kummer W, Hain T, Goesmann A, Bellusci S, Seeger W, Braun T, Herold S. 2020. Multilineage murine stem cells generate complex organoids to model distal lung development and disease. EMBO J 39:e103476.
  • Schmoldt C, Vazquez-Armendariz AI, Shalashova I, Selvakumar B, Bremer CM, Peteranderl C, Wasnick R, Witte B, Gattenlohner S, Fink L, Vadasz I, Morty RE, Pleschka S, Seeger W, Gunther A, Herold S. 2019. IRE1 Signaling As a Putative Therapeutic Target in Influenza Virus-induced Pneumonia. Am J Respir Cell Mol Biol 61:537-540.
  • Salwig I, Spitznagel B, Vazquez-Armendariz AI, Khalooghi K, Guenther S, Herold S, Szibor M, Braun T. 2019. Bronchioalveolar stem cells are a main source for regeneration of distal lung epithelia in vivo. EMBO J 38.
  • El Agha E, Moiseenko A, Kheirollahi V, De Langhe S, Crnkovic S, Kwapiszewska G, Szibor M, Kosanovic D, Schwind F, Schermuly RT, Henneke I, MacKenzie B, Quantius J, Herold S, Ntokou A, Ahlbrecht K, Braun T, Morty RE, Gunther A, Seeger W, Bellusci S. 2017. Two-Way Conversion between Lipogenic and Myogenic Fibroblastic Phenotypes Marks the Progression and Resolution of Lung Fibrosis. Cell Stem Cell 20:261-273 e3.
  • Quantius J, Schmoldt C, Vazquez-Armendariz AI, Becker C, El Agha E, Wilhelm J, Morty RE, Vadasz I, Mayer K, Gattenloehner S, Fink L, Matrosovich M, Li X, Seeger W, Lohmeyer J, Bellusci S, Herold S. 2016. Influenza Virus Infects Epithelial Stem/Progenitor Cells of the Distal Lung: Impact on Fgfr2b-Driven Epithelial Repair. PLoS Pathog 12:e1005544.
  • Peteranderl C, Morales-Nebreda L, Selvakumar B, Lecuona E, Vadasz I, Morty RE, Schmoldt C, Bespalowa J, Wolff T, Pleschka S, Mayer K, Gattenloehner S, Fink L, Lohmeyer J, Seeger W, Sznajder JI, Mutlu GM, Budinger GR, Herold S. 2016. Macrophage-epithelial paracrine crosstalk inhibits lung edema clearance during influenza infection. J Clin Invest 126:1566-80.
  • Herold S, Hoegner K, Vadasz I, Gessler T, Wilhelm J, Mayer K, Morty RE, Walmrath HD, Seeger W, Lohmeyer J. 2014. Inhaled granulocyte/macrophage colony-stimulating factor as treatment of pneumonia-associated acute respiratory distress syndrome. Am J Respir Crit Care Med 189:609-11.
  • Unkel B, Hoegner K, Clausen BE, Lewe-Schlosser P, Bodner J, Gattenloehner S, Janssen H, Seeger W, Lohmeyer J, Herold S. 2012. Alveolar epithelial cells orchestrate DC function in murine viral pneumonia. J Clin Invest 122:3652-64.
  • Herold S, Tabar TS, Janssen H, Hoegner K, Cabanski M, Lewe-Schlosser P, Albrecht J, Driever F, Vadasz I, Seeger W, Steinmueller M, Lohmeyer J. 2011. Exudate macrophages attenuate lung injury by the release of IL-1 receptor antagonist in gram-negative pneumonia. Am J Respir Crit Care Med 183:1380-90.
  • Cakarova L, Marsh LM, Wilhelm J, Mayer K, Grimminger F, Seeger W, Lohmeyer J, Herold S. 2009. Macrophage tumor necrosis factor-alpha induces epithelial expression of granulocyte-macrophage colony-stimulating factor: impact on alveolar epithelial repair. Am J Respir Crit Care Med 180:521-32.
  • Herold S, Steinmueller M, von Wulffen W, Cakarova L, Pinto R, Pleschka S, Mack M, Kuziel WA, Corazza N, Brunner T, Seeger W, Lohmeyer J. 2008. Lung epithelial apoptosis in influenza virus pneumonia: the role of macrophage-expressed TNF-related apoptosis-inducing ligand. J Exp Med 205:3065-77.