Sub-neutralizing levels of antibodies against RSV F protein enhance RSV infection via Fc-FcγR interactions
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Updated: Sep 18, 2025
An Improved and High Throughput Respiratory Syncytial Virus RSV Micro-neutralization Assay
Published on: January 26, 2019
Tingting Luo1, Xin Zhao1, Yi Lu1
1Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation base of Child Development and Critical Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing, China.
Abstract:
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.
Insights
Sub-neutralizing antibodies against respiratory syncytial virus (RSV) can worsen infections through antibody-dependent enhancement (ADE). This occurs via Fc-Fc gamma receptor interactions, involving FcγRI and TLR4 signaling, leading to increased inflammation and viral replication.
Area of Science:
- Immunology
- Virology
- Molecular Biology
Background:
- Respiratory syncytial virus (RSV) causes severe infant respiratory infections.
- Antibody-dependent enhancement (ADE) complicates vaccine and antibody development for RSV.
- Sub-neutralizing antibodies can paradoxically increase RSV pathogenesis.
Purpose of the Study:
- To elucidate the molecular mechanisms of ADE induced by sub-neutralizing anti-RSV F protein antibodies.
- To identify the cellular receptors and signaling pathways involved in RSV ADE.
- To understand the role of inflammation in amplifying RSV ADE.
Main Methods:
- Investigated RSV attachment, endocytosis, replication, and release in the presence of sub-neutralizing antibodies.
- Utilized nirsevimab Fab fragments to block F protein interactions.
- Performed blockade experiments using FcγRI and TLR4 inhibitors.
- Analyzed intracellular inflammatory signaling pathways and cytokine secretion (IL-1β, IL-6, TNF-α).
Main Results:
- Sub-neutralizing anti-RSV F antibodies enhanced RSV entry via Fc-Fc gamma receptor (FcγR) interactions.
- ADE was abrogated by blocking F protein with nirsevimab Fab fragments.
- FcγRI was identified as the primary receptor for ADE, with synergistic involvement of TLR4.
- ADE induced cytokine secretion, which upregulated FcγRs, creating a positive feedback loop.
Conclusions:
- Sub-neutralizing antibodies promote RSV entry and replication via FcγRs, leading to ADE.
- RSV ADE pathogenesis involves coordinated FcγRI and TLR4 signaling, amplified by cytokine-induced FcγR upregulation.
- Findings offer insights for developing improved next-generation RSV vaccines and therapeutics.
