Comparison of SARS-CoV-2 variant pathogenicity in a long-COVID Syrian hamster model.

The SARS-CoV-2 pandemic has infected over 700 million people, and a substantial proportion develop post-acute sequelae of COVID-19, a disorder marked by persistent, multi-organ symptoms. Elucidating the underlying pathophysiology; and how it varies by viral lineage; is critical for guiding therapy. Syrian golden hamsters develop transient but non-lethal illness that parallels human disease and are therefore a model to investigate post-acute phase pathology with different viral variants. Hamsterswere infection with WT (B1), Alpha (B.1.1.7) or Beta (B.1.351) variants and monitored for 28 days for clinical signs and viral shedding. Lungs, nasal turbinates, heart, kidneys and spleen were collected at 14- and 28-days post-infection for quantitative histopathological analysis. All viral variants produced similar acute disease, with peak viral loads on day 3 and maximal weight loss on day 7. Inflammation and fibrosis were evident in every infected group. Notably, WT and Alpha variants caused greater lung, cardiac, and renal fibrosis than the Beta variant, while splenic germinal-center expansion was most pronounced in animals infected with the Alpha variant. These findings establish that SARS-CoV-2 leaves variant-dependent post-acute multi-organ damage in hamsters, with WT and Alpha inducing the most severe pathology. This model captures variant-dependent post-acute organ injury and provides a quantitative framework for evaluating anti-fibrotic interventions.