Project description:The continued evolution of SARS-CoV-2 has produced variants with enhanced transmissibility despite reduced binding affinity to the canonical entry receptor ACE2, suggesting the involvement of additional host factors. Here, we integrate large-scale sequence analysis, structure-informed machine learning, biochemical assays, cell-based entry models, and in vivo infection studies to examine receptor usage diversification in recent SARS-CoV-2 variants. We find that multiple post-Omicron lineages, including XBB-derived variants, exhibit increased functional engagement of dipeptidyl peptidase 4 (DPP4), accompanied by reduced reliance on ACE2-mediated entry in defined experimental contexts. In human DPP4 knock-in mice, representative XBB variants display enhanced replication with limited pulmonary pathology. Together, these findings support a model in which SARS-CoV-2 evolution is characterized by diversification of receptor engagement strategies, highlighting DPP4 as a functionally relevant entry factor that may contribute to viral fitness under immune pressure.

2026-04-28 | GSE328992 | GEO

Single-Cell RNA Expression Profiling of ACE2, the Receptor of SARS-CoV-2.

Project description: Not available

| S-EPMC7462411 | biostudies-literature

SARS-CoV-2 cell receptor gene ACE2 -mediated immunomodulation in breast cancer subtypes.

Project description: Not available

| S-EPMC7643628 | biostudies-literature

SARS-CoV-2 receptor ACE2 protein expression in serum is significantly associated with age.

Project description: Not available

| S-EPMC8278339 | biostudies-literature

Expression of ACE2, the SARS-CoV-2 receptor, and TMPRSS2 in prostate epithelial cells.

Project description: Not available