A Selenium-Deficient Mouse Model of Mouse-Adapted SARS-CoV-2 Demonstrates Variant Emergence Observed in SARS-CoV-2 Pandemic Variants

Authors

Graham, M. E., Oluwasemowo, O., Murugesh, D. K., Rangel, M. V., Kimbrel, J. A., Avila-Herrera, A., Thiessen, J., Zemla, A., Phillips, A. M., Collette, N., Weilhammer, D., Borucki, M. K.

Abstract

Host selenium deficiency has been shown to generate novel genetic variants in RNA viruses. With the predicted rise of selenium deficiency globally, we sought to determine if host selenium deficiency can be a predictive factor for RNA virus variant emergence. We utilized a selenium-deficient BALB/c mouse model to investigate how host selenium status influences the emergence of viral variants in mouse-adapted SARS-CoV-2. Mice were maintained on control or selenium-deficient diets and subjected to sequential rounds of diet-matched viral passage to generate diet-specific virus populations. Deep sequencing of passaged viral populations revealed that selenium-deficient passage drove a marked increase in inter-host genomic heterogeneity and produced a distinct mutational profile relative to control passage. Eighteen mutations were identified as unique to selenium-deficient passage, including variants previously observed during natural human SARS-CoV-2 evolution. These mutations were largely maintained at sub-consensus frequencies, indicating that selenium deficiency can expand the viral quasispecies landscape that enrichs reservoirs of adaptive potential. To determine how this altered mutant spectrum affected pathogenesis, we challenged normal diet-fed adult and aged BALB/c mice with control- or selenium-deficient-passaged virus. Although overt differences in weight loss, survival, and viral burden were generally modest, selenium-deficient-passaged virus induced pronounced increases in antiviral cytokine expression. Together, these findings identify host selenium deficiency as a driver of RNA virus population diversification and show that nutritionally stressed animal models can reproducibly generate mutations observed in nature.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 27 Aug 2026.

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