SARS-CoV-2 infection results in a unique lung proteome long after virus resolution in the hamster

Long COVID or post-acute sequelae of COVID-19 (PASC) remains an ongoing public health issue that causes impairment for those afflicted and diminishes their ability to contribute to society. To address the host response underpinning respiratory PASC, we used the Golden Syrian hamster model infected with ancestral SARS-CoV-2 and examined its lung proteome in a longitudinal experiment. We infected young 6-week old male and female hamsters with 10⁵ TCID₅₀ of virus via the intranasal route and sampled the lung at 1, 3, 5, and 31 days post infection (dpi). We compared the infected lung proteome to that of uninfected sex-matched controls. We found almost no differences in protein levels at 1 dpi, with hundreds at 3 dpi, and thousands at 5 dpi. Many overlapping differential protein levels and pathways were seen in both sexes at 3 and 5 dpi including the Coagulation and Complement cascades. Notably, we found differences between the sexes at 31 dpi which included many targets with decreased levels of protein in the males. We also noted an increase in 7 proteins in both sexes at 31 dpi including proteins responsible for airway mucosal layer integrity such as Mucin 5B and Calcium-activated chloride channel regulator 1. Longitudinally, 38 proteins were changed in levels across more than one timepoint in the males but only three proteins were in the females, Secretoglobin family 1 A member 1, Poly [ADP-ribose] polymerase, and Apolipoprotein D. Overall, we show that there are changes to the lung proteome at 31 dpi, a time when no SARS-CoV-2 remains, and that there are sex differences in that proteome after infection with the ancestral strain. We conclude that biological sex should be examined as a variable when testing medical countermeasures for PASC in the Golden Syrian hamster due to host differences between the sexes.