PT  - JOURNAL ARTICLE
AU  - Laura Heydemann
AU  - Malgorzata Ciurkiewicz
AU  - Georg Beythien
AU  - Kathrin Becker
AU  - Klaus Schughart
AU  - Stephanie Stanelle-Bertram
AU  - Berfin Schaumburg
AU  - Nancy Mounogou-Kouassi
AU  - Sebastian Beck
AU  - Martin Zickler
AU  - Mark Kühnel
AU  - Gülsah Gabriel
AU  - Andreas Beineke
AU  - Wolfgang Baumgärtner
AU  - Federico Armando
TI  - Hamsters are a model for COVID-19 alveolar regeneration mechanisms: an opportunity to understand post-acute sequelae of SARS-CoV-2
AID  - 10.1101/2022.11.17.515635
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.11.17.515635
4099  - http://biorxiv.org/content/early/2022/11/18/2022.11.17.515635.short
4100  - http://biorxiv.org/content/early/2022/11/18/2022.11.17.515635.full
AB  - 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 TP53 at 6- and 14-days post infection (dpi), indicating a prolonged arrest 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.Competing Interest StatementThe authors have declared no competing interest.