The Y498T499-SARS-CoV-2 Spike (S) protein interacts poorly with rat ACE2 and does not affect the rat lung.

• DOI: 10.1099/acmi.0.000839.v2
• Publication Date: 2024-09-04T12:27:22Z
• Authors: Amy L Green; Dylan Debellis; Evangeline Cowell; Roman V Lenchine; Timothy Penn; Luke P Kris; James McEvoy-May; Shailesh Bihari; Dani-Louise Dixon; Jillian M Carr
• Keywords: Affect; spike protein; Coronavirus

The rat is a useful laboratory model for respiratory disease, and SARS-CoV-2 proteins such as the spike (S) protein can induce inflammation. This study has investigated ability of Q498Y, P499T (QP-YT) amino acid change described in S-protein mouse adapted MA strain, to interact with angiotensin converting enzyme-2 (ACE2) stimulate responses lung. Using real-time S-ACE2 quantitative fusion assay, ancestral L452R fuses human, but not ACE2 expressed on HEK293 cells. QP-YT retains fuse human ACE2, increases binding ACE2. Although lower lung contains both TMPRSS2 target cells, intratracheal delivery or pseudotyped lentivirus did measurable changes, inflammatory infiltration, innate mRNA responses. Isolation primary cells from alveoli demonstrated presence expressing TMPRSS2. Infection these however was observed poorly infected Analysis changes across interface highlights Y498 interaction H353 likely facilitator also other acids that could improve this interaction. Thus, lungs contain receptors variant bind does result infection Further enhance utility defining role driving