Exacerbated Hepatic Stress and Systemic Metabolic Disruption Driven by SARS-CoV-2 P.1 Variant in K18-hACE2 Mice

While severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been extensively studied in the context of pulmonary disease, its impact on metabolic organs remains poorly understood, particularly across experimental models.

In this study, we investigated how infection with the SARS-CoV-2 B.1 and P.1 variants affects metabolic tissues in K18-hACE2 transgenic mice. Both viral variants caused significant body weight loss and clinical deterioration as early as 3 days postinfection, with the P.1 variant leading to higher lethality than B.1. Notably, this increased disease severity was not associated with elevated viral loads in the lungs. Viral RNA was also detected in both the liver and adipose tissues, indicating that these metabolic organs are permissive to infection in this model. Histological analysis revealed disrupted hepatic parenchymal organization in P.1-infected mice, even in the absence of substantial immune cell infiltration. Despite this, liver expression of pro-inflammatory cytokines was significantly elevated, particularly following P.1 infection. These changes were not accompanied by liver fibrosis; however, tissue disorganization was confirmed using two-photon excitation fluorescence imaging. In parallel, systemic metabolic alterations were observed, including increased ketogenesis, reduced adipose tissue mass, hepatic glycogen depletion, and alterations in glucose homeostasis. These metabolic disturbances likely contributed to the observed weight loss and reflect a host response to viral-induced energy stress.

Together, these findings demonstrate that SARS-CoV-2 infects metabolic tissues beyond the lungs and that the P.1 variant induces exacerbated hepatic stress and more severe disease outcomes in this experimental model.