Respiratory long COVID in aged hamsters features impaired lung function post-exercise with bronchiolization and fibrosis

Laura Heydemann, Małgorzata Ciurkiewicz, Theresa Störk, Isabel Zdora, Kirsten Hülskötter, Katharina Manuela Gregor, Lukas Mathias Michaely, Wencke Reineking, Tom Schreiner, Georg Beythien, Asisa Volz, Tamara Tuchel, Christian Meyer zu Natrup, Lisa-Marie Schünemann, Sabrina Clever, Timo Henneck, Maren Köckritz-Blickwede, Dirk Schaudien, Karl Rohn, Klaus Schughart, Robert Geffers, Mika K. Kaneko, Yukinari Kato, Carina Gross, Georgios Amanakis, Andreas Pavlou, Wolfgang Baumgärtner () and Federico Armando
Additional contact information
Laura Heydemann: University of Veterinary Medicine Foundation
Małgorzata Ciurkiewicz: University of Veterinary Medicine Foundation
Theresa Störk: University of Veterinary Medicine Foundation
Isabel Zdora: University of Veterinary Medicine Foundation
Kirsten Hülskötter: University of Veterinary Medicine Foundation
Katharina Manuela Gregor: University of Veterinary Medicine Foundation
Lukas Mathias Michaely: University of Veterinary Medicine Foundation
Wencke Reineking: University of Veterinary Medicine Foundation
Tom Schreiner: University of Veterinary Medicine Foundation
Georg Beythien: University of Veterinary Medicine Foundation
Asisa Volz: University of Veterinary Medicine Foundation
Tamara Tuchel: University of Veterinary Medicine Foundation
Christian Meyer zu Natrup: University of Veterinary Medicine Foundation
Lisa-Marie Schünemann: University of Veterinary Medicine Foundation
Sabrina Clever: University of Veterinary Medicine Foundation
Timo Henneck: University of Veterinary Medicine Foundation
Maren Köckritz-Blickwede: University of Veterinary Medicine Foundation
Dirk Schaudien: Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM)
Karl Rohn: University of Veterinary Medicine Foundation
Klaus Schughart: University of Tennessee Health Science Center
Robert Geffers: Helmholtz Centre for Infection Research (HZI)
Mika K. Kaneko: Tohoku University
Yukinari Kato: Tohoku University
Carina Gross: Hanover Medical School (MHH)
Georgios Amanakis: Hanover Medical School (MHH)
Andreas Pavlou: a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School
Wolfgang Baumgärtner: University of Veterinary Medicine Foundation
Federico Armando: University of Parma

Nature Communications, 2025, vol. 16, issue 1, 1-24

Abstract: Abstract Long-term consequences of SARS-CoV-2 infection affect millions of people and strain public health systems. The underlying pathomechanisms remain unclear, necessitating further research in appropriate animal models. This study aimed to characterize the trajectory of lung regeneration over 112 days in the male hamster model by combining morphological, transcriptomic and functional readouts. We demonstrate that in the acute phase, SARS-CoV-2 Delta-infected, male, aged hamsters show a severe impairment of lung function at rest. In the chronic phase, similar impairments persisted up to 7 weeks post-infection but were only evident after exercise on a rodent treadmill. The male hamster model recapitulates chronic pulmonary fibrotic changes observed in many patients with respiratory long COVID, but lacks extra-pulmonary long-term lesions. We show that sub-pleural and interstitial pulmonary fibrosis as well as alveolar bronchiolization persist until 112 dpi. Interestingly, CK8+ alveolar differentiation intermediate (ADI) cells are becoming less prominent in the alveolar proliferation areas from 28 dpi on. Instead, CK14+ airway basal cells and SCGB1A1+ club cells, expressing cell proliferation markers, mainly populate alveolar bronchiolization areas at later time-points. We postulate that pulmonary fibrosis and SCGB1A1+ club cell-rich areas of alveolar bronchiolization represent potential risk factors for other diseases in long-COVID survivors.

Date: 2025
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DOI: 10.1038/s41467-025-57267-x

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