Hamsters are a model for COVID-19 alveolar regeneration mechanisms: an opportunity to understand post-acute sequelae of SARS-CoV-2 (preprint)

A relevant number of coronavirus disease 2019 (COVID-19) survivors suffers from post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PASC). Current evidence suggests a dysregulated alveolar regeneration in COVID-19 as a possible explanation for respiratory PASC symptoms, a phenomenon which deserves further investigation in a suitable animal model. This study investigates morphologic and transcriptomic features of alveolar regeneration in SARS-CoV-2 infected Syrian golden hamsters. We demonstrate that CK8+ alveolar differentiation intermediate (ADI) cells accumulate following SARS-CoV-2-induced diffuse alveolar damage. A subset of ADI cells shows nuclear accumulation of p53 at 6- and 14-days post infection (dpi), indicating a prolonged block in the ADI state. Transcriptome data shows the expression of gene signatures driving ADI cell senescence, epithelial-mesenchymal transition, and angiogenesis. Moreover, we show that multipotent CK14+ airway basal cell progenitors migrate out of terminal bronchioles, aiding alveolar regeneration. At 14 dpi, persistence of ADI cells, peribronchiolar proliferates, M2-type macrophages, and sub-pleural fibrosis is observed, indicating incomplete alveolar restoration. The results demonstrate that the hamster model reliably phenocopies indicators of a dysregulated alveolar regeneration of COVID-19 patients. The study provides a suitable translational model for future research on the pathomechanims of PASC and testing of prophylactic and therapeutical approaches.

SARS-CoV-2 Omicron variant causes mild pathology in the upper and lower respiratory tract of Syrian golden hamsters (Mesocricetus auratus) (preprint)

Since its discovery in 2019, multiple variants of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) have been identified worldwide. The present study investigates virus spread and associated pathology in the upper and lower respiratory tracts in the early phase of SARS-CoV-2 Omicron infection in the Syrian golden hamster (Mesocricetus auratus) in comparison to previous identified variants of concern (VOCs). Syrian golden hamsters were infected intranasally with SARS-CoV-2 614G or with VOCs Gamma, Delta and Omicron. Pathological changes both in the upper and lower respiratory tract of VOC Omicron infected hamsters were milder than those caused by the other investigated strains. VOC Omicron infection caused only a mild rhinitis with mild involvement of the olfactory epithelium and minimal lesions in the lung with frequent sparing of the alveolar compartment. Similarly, viral antigen detection as well as infectious SARS-CoV-2 titers were lower in upper and lower respiratory tract of VOC Omicron infected hamsters. These findings demonstrate that the SARS-CoV-2 VOC Omicron variant has a decreased pathogenicity for both the upper and lower respiratory tract of Syrian golden hamsters.