Mechanism of human antibody-mediated neutralization of Marburg virus

Area of Science:

• Virology
• Immunology
• Structural Biology

Background:

• The precise mechanisms by which neutralizing antibodies inhibit Marburg virus (MARV) remain largely unknown.
• Understanding these mechanisms is crucial for developing effective antiviral therapies against filoviruses.

Purpose of the Study:

• To elucidate the mechanism of action of neutralizing antibodies against Marburg virus (MARV).
• To characterize the binding sites and structural interactions of MARV-specific neutralizing antibodies.

Main Methods:

• Isolation and characterization of neutralizing antibodies from a MARV survivor.
• Binding assays to assess antibody interaction with MARV and Ebola virus (EBOV) glycoproteins (GP).
• Single-particle cryo-electron microscopy (cryo-EM) to determine structures of antibody-GP complexes.

Main Results:

• A panel of neutralizing antibodies targeting MARV glycoprotein (GP) was identified, all binding to a single major antigenic site.
• Several antibodies demonstrated cross-reactivity with Ebola virus (EBOV) GP.
• Cryo-EM revealed that neutralizing antibodies bind to MARV GP near the receptor-binding site, a site accessible despite the glycan cap and mucin-like domain.
• Unlike MARV GP, EBOV GP binding was hindered by its glycan cap and mucin-like domain.

Conclusions:

• MARV-neutralizing antibodies inhibit the virus by binding to the exposed receptor-binding site on infectious virions.
• This binding mechanism represents a novel strategy for filovirus inhibition.
• The distinct accessibility of the MARV GP receptor-binding site compared to EBOV GP influences antibody neutralization efficacy.