ORIGINAL RESEARCH article
Front. Immunol.
Sec. Viral Immunology
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1594937
Sub-Neutralizing Levels of Antibodies against RSV F Protein Enhance RSV Infection via Fc-FcγR interactions
Provisionally accepted
- Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, Chongqing, China
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Respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract infections in infants, and antibody-dependent enhancement (ADE) presents a significant challenge in vaccine and antibody development. This study investigated the molecular mechanism of ADE mediated by sub-neutralizing antibodies against RSV F protein. We demonstrated that anti-RSV F antibody could facilitate RSV attachment and endocytosis into cells via Fc-Fc gamma receptor (FcγR) interactions while only at sub-neutralizing levels, it increased RSV replication and release, thereby inducing ADE. ADE was abrogated following the secondary occlusion of F protein using nirsevimab Fab fragments. During ADE, intracellular inflammatory signaling pathways were overactivated, resulting in elevated secretion of pro-inflammatory factors (IL-1β, IL-6, TNF-α). FcγRⅠ was identified as the dominant receptor of ADE through blockade experiments, and dual inhibition of FcγRⅠ and TLR4 abolished ADE, highlighting their synergistic role. Furthermore, ADE-induced cytokines upregulated FcγRs expression, creating a self-reinforcing inflammatory loop. Overall, our findings indicated that (1) sub-neutralizing F-specific antibodies increase RSV entry via FcγRs, whereby partially unsealed F protein allows subsequent membrane fusion and enhances replication; (2) RSV ADE pathogenesis involves the coordination of FcγRⅠ and TLR4 signaling pathways, and is amplified by cytokine-driven upregulation of FcγRs. These findings are helpful for the development of next-generation antibody and vaccine against RSV.
Keywords: respiratory syncytial virus, nirsevimab, Antibody-Dependent Enhancement, Fc gamma receptor, Viral lifecycle
Received: 17 Mar 2025; Accepted: 29 Apr 2025.
Copyright: © 2025 Luo, Zhao, Lu, Tan, Peng, Zhong, Ma, Mei, Huaqin and Tian. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Daiyin Tian, Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, Chongqing, China
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