Quantitative Tissue Proteomics Reveals Protein Signatures Associated with SARS-CoV‑2 Variant Infection in Hamsters

Since its emergence in 2019, circulating SARS-CoV-2 has been dominated by waves of genetically distinct variants with varying pathogenicity. Understanding the multidimensional responses to SARS-CoV-2 infection and their associations with pathogenesis is critical for developing therapies to prevent severe illness and death. Here, we applied quantitative proteome and phosphoproteome analyses to compare host responses to infections with an ancestral variant (WA-1/2020), a Delta variant (B.1.617.2), and an Omicron variant (BA.1) of SARS-CoV-2 in Syrian golden hamster tissues at 5 days postinfection, when peak inflammatory responses were observed. As has been observed by others, animals infected with the Delta variant lost more weight than those infected with other variants, and this effect was associated with decreased cilia proteins in the trachea tissue and increased signatures of fibrosis in lung tissue. Phosphoproteome analysis revealed a downregulation of Raf-MEK-ERK signaling across all variants, suggesting a suppressed proliferative response in tissues following SARS-CoV-2 infection. These data provide critical in vivo confirmation of observations from in vitro studies and provide a quantitative tissue- and SARS-CoV-2 variant-specific resource of proteome and phosphoproteome responses.