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

Nat Commun. 2025 Feb 28;16(1):2080. doi: 10.1038/s41467-025-57267-x.

Laura Heydemann ^# ¹, Małgorzata Ciurkiewicz ^# ¹, Theresa Störk ¹, Isabel Zdora ¹, Kirsten Hülskötter ¹, Katharina Manuela Gregor ¹, Lukas Mathias Michaely ¹, Wencke Reineking ¹, Tom Schreiner ¹, Georg Beythien ¹, Asisa Volz ² ³, Tamara Tuchel ² ³, Christian Meyer Zu Natrup ² ³, Lisa-Marie Schünemann ² ³, Sabrina Clever ² ³, Timo Henneck ³ ⁴, Maren von Köckritz-Blickwede ³ ⁴, Dirk Schaudien ⁵, Karl Rohn ⁶, Klaus Schughart ⁷ ⁸, Robert Geffers ⁹, Mika K Kaneko ¹⁰, Yukinari Kato ¹⁰, Carina Gross ¹¹, Georgios Amanakis ¹¹, Andreas Pavlou ¹², Wolfgang Baumgärtner ^# ¹³, Federico Armando ^# ¹⁴

Affiliations

1 Department of Pathology, University of Veterinary Medicine Foundation, Hanover, Germany.
2 Department of Virology, University of Veterinary Medicine Foundation, Hanover, Germany.
3 Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Foundation, Hanover, Germany.
4 Department of Biochemistry, University of Veterinary Medicine Foundation, Hanover, Germany.
5 Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hanover, Germany.
6 Department of Biometry, Epidemiology and Data Management, University of Veterinary Medicine Foundation, Hanover, Germany.
7 Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN, USA.
8 Institute of Virology Münster, University of Münster, Münster, Germany.
9 Helmholtz Centre for Infection Research (HZI), Brunswick, Germany.
10 Department of antibody drug development, Tohoku University, Sendai, Miyagi, Japan.
11 Department of Cardiology and Angiology, Hanover Medical School (MHH), Hanover, Germany.
12 Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany.
13 Department of Pathology, University of Veterinary Medicine Foundation, Hanover, Germany. Wolfgang.baumgaertner@tiho-hannover.de.
14 Pathology Unit, Department of Veterinary Science, University of Parma, Parma, Italy.
# Contributed equally.

PMID: 40021627 DOI: 10.1038/s41467-025-57267-x

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.

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