Persistent alveolar bronchiolization, interstitial fibrosis and impaired lung function post-exercise are features of long-COVID in SARS-CoV-2-Delta variant infected aged hamsters

Abstract

Long-term consequences of SARS-CoV-2 infection affect the life quality of millions of people and pose a heavy burden on the public health sector. The underlying causes, pathomechanisms and morphological correlates are still largely unknown and further research in appropriate animal models is needed. The goal of the study was to characterize the trajectory of lung regeneration over a period of 112 days in the hamster model by combining morphological, transcriptome analysis 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 in a resting state. In the chronic phase of the disease, similar impairments are appreciable until 7 weeks post infection only after exercise on a rodent treadmill. The hamster model recapitulates chronic pulmonary fibrotic changes observed in many patients with respiratory long COVID, but does not show 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.