Structural basis for the synergistic neutralization of coxsackievirus B1 by a triple-antibody cocktail

Area of Science:

• Virology
• Immunology
• Structural Biology

Background:

• Coxsackievirus B1 (CVB1) is an emerging pathogen linked to severe neonatal diseases and type 1 diabetes.
• Neutralizing antibodies (nAbs) are crucial for inhibiting viral entry and pathogenesis.

Purpose of the Study:

• To characterize the binding and therapeutic efficacies of three CVB1-specific nAbs.
• To elucidate the structural basis of antibody-mediated inhibition of CVB1 infection.

Main Methods:

• High-resolution cryo-electron microscopy (cryo-EM) to determine antibody-virus complex structures.
• In vitro neutralization assays to assess antibody efficacy.
• In vivo studies in neonatal and non-obese diabetic mouse models to evaluate therapeutic protection.

Main Results:

• Three nAbs recognize distinct epitopes on the CVB1 capsid VP2 protein, specifically the EF loop, with overlapping binding regions.
• Antibodies perturb capsid-receptor interactions across various viral particle forms.
• Combinations of nAbs induce synergistic neutralization through stepwise capsid transition and virion disruption.
• A three-antibody cocktail demonstrated protection against lethal CVB1 challenge in neonatal mice and reduced pancreatitis and viral replication in a type 1 diabetes model.

Conclusions:

• CVB1-specific nAbs can be rationally designed to target viral capsid structures.
• Synergistic neutralization by antibody combinations offers a potent therapeutic strategy against picornaviruses like CVB1.
• This nAb cocktail shows promise as a therapeutic intervention for CVB1-related diseases, including those associated with type 1 diabetes.