Nature Communications | FcRn interaction with HAstV reveals viral entry mechanism

This study presents the first crystal structure of the FcRn and HAstV1 spike domain complex, revealing the molecular mechanism by which HAstV invades the host through binding with FcRn. It also demonstrates that neutralizing antibodies and FcRn inhibitors can effectively block this interaction, providing a theoretical basis for vaccine and antibody therapy development.

 

Literature Overview
This article, 'Structure of the human astrovirus capsid spike in complex with the neonatal Fc receptor', published in the journal Nature Communications, reviews and summarizes the structural and functional insights into the interaction between human astrovirus (HAstV) and the FcRn receptor, offering critical information on viral receptor binding and neutralizing antibody mechanisms.

Background Knowledge
HAstV is one of the major pathogens causing viral gastroenteritis in children worldwide; however, its infection mechanism has remained unclear for a long time. Recently, FcRn was identified as a functional receptor for HAstV, opening new avenues for studying viral entry. This study reports the crystal structure of the FcRn-HAstV1 spike complex determined by X-ray crystallography, combined with mutagenesis and competition binding assays, to reveal three critical amino acid residues involved in receptor binding. Additionally, the study evaluates the blocking effects of neutralizing antibodies and FcRn inhibitors such as nipocalimab on HAstV binding, providing structural and functional insights for antiviral therapeutic development. Although cell and organoid models have been used to study HAstV infection, small animal models remain a bottleneck. This study provides novel molecular targets and a structural framework for vaccine development and antiviral drug screening, offering significant translational potential.

 

 

Research Methods and Experiments
The research team employed recombinant expression and purification of FcRn and the HAstV1 spike protein, and used biolayer interferometry (BLI) and size-exclusion chromatography (SEC) to evaluate binding kinetics and complex formation. Site-directed mutagenesis was performed to analyze the role of three key residues (K467, Y475, K514) in receptor binding, while competition binding assays assessed the impact of IgG, HSA, and nipocalimab on HAstV1 spike-FcRn interaction. Furthermore, the binding between mouse FcRn and the HAstV1 spike was tested to explore the potential for developing small animal models.

Key Conclusions and Perspectives

• FcRn binds to the HAstV1 spike under both neutral and weakly acidic conditions, with higher affinity observed under weakly acidic conditions
• SEC analysis indicates that FcRn forms a 2:2 complex with the HAstV1 spike, similar to its binding mode with IgG
• Crystal structure reveals that three highly conserved spike residues (K467, Y475, K514) are critical for FcRn binding
• Mutagenesis analysis shows that K467A, Y475A, and K514A mutations significantly reduce binding affinity, while the triple mutant completely abolishes binding
• HAstV1 spike competes with IgG for FcRn binding, but can simultaneously bind with HSA
• Neutralizing antibodies 2D9 and 3E8 block FcRn-spike interaction via steric hindrance
• Although the HAstV1 spike binds to mouse FcRn, mice still do not support viral infection, suggesting additional host-specific barriers

Research Significance and Prospects
This study provides the first structural insights into the HAstV-FcRn interaction, establishing a key structural foundation for developing neutralizing antibodies and vaccines. Future studies could focus on the precise role of FcRn in the HAstV life cycle, such as in uncoating or endosomal trafficking, and explore strategies for developing broadly protective vaccines targeting this interface. Further investigation into cross-reactivity between neutralizing antibodies and FcRn binding could enhance understanding of antibody-based therapies and guide optimization of therapeutic antibody development.

 

 

Conclusion
Through structural biology and biochemical analyses, this study systematically elucidates the binding mechanism between the HAstV spike protein and FcRn, supporting FcRn as a critical receptor for HAstV infection and providing a foundation for the development of neutralizing antibodies and small-molecule inhibitors. The observed binding of the HAstV1 spike to mouse FcRn also suggests that genetically engineered mouse models could be developed for HAstV studies. Future research should focus on in vivo validation of FcRn's role in HAstV infection and the development of vaccines or therapeutic antibodies targeting this binding interface.

 

Adam Lentz, Sarah Lanning, Khurshid R Iranpur, Carlos F Arias, and Rebecca M DuBois. Structure of the human astrovirus capsid spike in complex with the neonatal Fc receptor. Nature Communications.