Susceptibility of different mouse strains to SARS-CoV-2 spike receptor-binding domain protein-induced lung inflammation: a comparative study

Transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) are widely used in research on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) due to their susceptibility to viral infection. However, the extent to which genetic differences among mouse strains affect inflammatory responses to the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein remains unclear. In this study, we compared the susceptibility of five commonly used mouse strains - DBA2, ICR, C3H/HeOuJ, BALB/c and C57BL/6J - to RBD-induced pulmonary inflammation. Histopathological analysis revealed that DBA2 and C57BL/6J mice exhibited significantly heightened inflammatory responses, characterized by increased angiotensin-converting enzyme 2 (ACE2) expression, macrophage infiltration, upregulation of proinflammatory cytokines (e.g. IL-1<i>β</i>, TNF-<i>α</i>) and activation of the IL-6/STAT3 and nicotinamide adenine dinucleotide phosphate oxidase pathways. These responses were markedly attenuated by pretreatment with an anti-ACE2 antibody, supporting a potential role of RBD-ACE2 interactions in driving inflammation, although ACE2-independent mechanisms cannot be excluded. Our findings suggest that DBA2 and C57BL/6J mice are particularly sensitive to RBD exposure and represent cost-effective and physiologically relevant models for studying ACE2-mediated lung inflammation and for evaluating therapeutic interventions targeting coronavirus disease 2019-related inflammatory mechanisms.