Comparison of the pathogenicity of multiple SARS-CoV-2 variants in mouse models

Qi Lv; Ming Liu; Feifei Qi; Mingya Liu; Fengdi Li; Ran Deng; Xujian Liang; Yanfeng Xu; Zhiqi Song; Yiwei Yan; Shuyue Li; Guocui Mou; Linlin Bao

doi:10.1002/ame2.70029

Abstract：Background: New variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to drive global epidemics and pose significant health risks. The pathogenicity of these variants evolves under immune pressure and host factors. Understanding these changes is crucial for epidemic control and variant research. Methods: Human angiotensin-converting enzyme 2 (hACE2) transgenic mice were intranasally challenged with the original strain WH-09 and the variants Delta, Beta, and Omicron BA.1, while BALB/c mice were challenged with Omicron subvariants BA.5, BF.7, and XBB.1. To compare the pathogenicity differences among variants, we conducted a comprehensive analysis that included clinical symptom observation, measurement of viral loads in the trachea and lungs, evaluation of pulmonary pathology, analysis of immune cell infiltration, and quantification of cytokine levels. Results: In hACE2 mice, the Beta variant caused significant weight loss, severe lung inflammation, increased inflammatory and chemotactic factor secretion, greater macrophage and neutrophil infiltration in the lungs, and higher viral loads with prolonged shedding duration. In contrast, BA.1 showed a significant reduction in pathogenicity. The BA.5, BF.7, and XBB.1 variants were less pathogenic than the WH-09, Beta, and Delta variants when infected in BALB/c mice. This was evidenced by reduced weight loss, diminished pulmonary pathology, decreased secretion of inflammatory factors and chemokines, reduced macrophage and neutrophil infiltration, as well as lower viral loads in both the trachea and lungs. Conclusion: In hACE2 mice, the Omicron variant demonstrated the lowest pathogenicity, while the Beta variant exhibited the highest. Pathogenicity of the Delta variant was comparable to the original WH-09 strain. Among BALB/c mice, Omicron subvariants BA.5, BF.7, and XBB.1 showed no statistically significant differences in virulence.