Intranasal prophylaxis with simple sACE2-Fc mutants protects against SARS-CoV-2 in mice by accelerating macrophage-mediated immunity
Presentation Time: 03:15 PM - 04:30 PM
Poster Board Number: B656
Abstract ID: 5335
Presenting Author:
Jingyi Wang , Intranasal prophylaxis with simple sACE2-Fc mutants protects against SARS-CoV-2 in mice by accelerating macrophage-mediated immunity at Chinese Univ. of Hong Kong, Chinese Univ. of Hong Kong Sch. of Biomed. Sci.
Abstract:
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), exhibiting rapid evolution and global circulation, can evade neutralization by monoclonal antibodies and convalescent/vaccine sera. Soluble angiotensin-converting enzyme 2 (sACE2) is a promising therapeutic due to conserved binding to SARS-CoV-2 spike, but has limited clinical application. Our goal was to develop sACE2 decoys for effective protection against SARS-CoV-2. We fused sACE2 with human IgG1 Fc (sACE2-Fc) and introduced minimal mutations to generate mutants with enhanced neutralization and deactivated enzymatic activity. These mutants showed improved and broad-spectrum neutralization against SARS-CoV-2 variants. Furthermore, adeno-associated virus (AAV)-based overexpression of the mutants in mice showed low immunogenicity and minimal renin-angiotensin system disruption. Administration of a promising mutant (B5-D3) provided efficient prophylaxis and ensured 100% survival in SARS-CoV-2-inoculated K18-hACE2 mice with dependence on Fc-mediated effector functions. Transcriptomic analysis revealed the crucial role of interferon and macrophage activities post infection. Immunohistochemistry staining indicated recruitment and early differentiation of macrophages in B5-D3-treated mice lungs. Our findings highlight the potential and mechanisms of simple sACE2-Fc mutants as an effective SARS-CoV-2 protection strategy.
Intranasal prophylaxis with simple sACE2-Fc mutants protects against SARS-CoV-2 in mice by accelerating macrophage-mediated immunity
Category
Poster and Podium (Block Symposium)