Differential effects of SARS-CoV-2-targeted infection of ATII, club cells, and macrophages on lung immunopathology and antiviral responses

The specific contributions of lung epithelial and immune cells to SARS-CoV-2–induced immunopathology and antiviral responses remain unclear. To address this, we generated mouse models with inducible expression of human angiotensin-converting enzyme 2 (hACE2) in specific lung cell types. Infection of mice expressing hACE2 on club cells triggered early type I interferon responses, limited viral replication, and caused transient, mild lung pathology. In contrast, hACE2-driven infection of type II alveolar epithelial cells (ATIIs) resulted in higher viral loads and moderate lung damage, accompanied by expansion of interstitial macrophages, virus-specific CD8+ T cell responses, and production of anti-SARS-CoV-2 IgG. Additionally, infection of mice expressing hACE2 on ATIIs increased CD11c+ CD8+ effector T cells and proinflammatory cytokines in the lungs, including IFN-γ, CXCL9, and CXCL10. However, neutralization of CXCL9 and CXCL10 exacerbated disease severity. Moreover, infection of mice with hACE2 targeted to ATIIs and macrophages led to severe lung injury, increased viral burden, enhanced T-cell and neutrophil infiltration, higher IgG responses, and sustained lung pathology. In contrast, hACE2 expression limited to endothelial cells was insufficient to promote SARS-CoV-2 replication in the lung or cause pathology. Together, these findings demonstrate that ACE2-driven infection of ATIIs, club cells, and macrophages plays distinct but cooperative roles in driving SARS-CoV-2-induced lung immunopathology and antiviral immunity.