Macrophage pyroptosis driven by Omicron variant’s distinct entry route underlies severe disease pathogenesis

Severe disease due to SARS-CoV-2 infection is a primary driver of healthcare burden throughout the pandemic. Although the overall pathogenicity of the Omicron variant is attenuated compared with earlier strains, mortality among patients who develop severe disease following Omicron infection remains substantial, and the underlying mechanisms remain unclear. By analyzing single-cell RNA sequencing data of bronchoalveolar lavage fluid from patients with severe disease caused by different viral strains, we find that, relative to those infected with the wild-type strain, patients infected with Omicron exhibit a markedly reduced abundance of macrophages, and this alteration is associated with poorer clinical outcomes. Mechanistic investigations reveal that Omicron preferentially infects macrophages via the endocytic pathway, inducing lysosomal damage and promoting the release of cathepsin L, which in turn hyperactivates the NLRP3-Caspase-1 pathway. This ultimately leads to enhanced pyroptosis of macrophages and massive secretion of inflammatory mediators, thereby potentially exacerbating disease progression. These findings highlight fundamental differences in immune responses elicited by distinct SARS-CoV-2 variants and underscore the need for variant-tailored strategies in clinical management. Analysis of the Omicron variant’s distinct endocytic entry route reveals how lysosomal damage and cathepsin L release hyperactivate macrophage pyroptosis, driving severe immunopathology and poor clinical outcomes