Structures of Two Human Astrovirus Capsid/Neutralizing Antibody Complexes Reveal Distinct Epitopes and Inhibition of Virus Attachment to Cells

• Published in: Journal of virology Vol. 96; no. 1; p. e0141521
• Main Authors: Ricemeyer, Lena, Aguilar-Hernández, Nayeli, López, Tomás, Espinosa, Rafaela, Lanning, Sarah, Mukherjee, Santanu, Cuellar, Carolina, López, Susana, Arias, Carlos F, DuBois, Rebecca M
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 12-01-2022
• Subjects: Amino Acid Sequence; Antibodies, Neutralizing - chemistry; Antibodies, Neutralizing - immunology; Antibodies, Viral - chemistry; Antibodies, Viral - immunology; Antibody Affinity - immunology; Astroviridae Infections - immunology; Astroviridae Infections - virology; Capsid - immunology; Capsid Proteins - chemistry; Capsid Proteins - immunology; Epitopes - chemistry; Epitopes - immunology; Host-Pathogen Interactions - immunology; Humans; Mamastrovirus - immunology; Models, Molecular; Molecular Conformation; Protein Binding; Structural Biology; Structure and Assembly; Structure-Activity Relationship; Virus Attachment; neutralizing antibodies; protein structure-function; astrovirus; capsid
• ISSN: 0022-538X; 1098-5514
• DOI: 10.1128/JVI.01415-21

Human astrovirus is an important cause of viral gastroenteritis worldwide. Young children, the elderly, and the immunocompromised are especially at risk for contracting severe disease. However, no vaccines exist to combat human astrovirus infection. Evidence points to the importance of antibodies in protecting healthy adults from reinfection. To develop an effective subunit vaccine that broadly protects against diverse astrovirus serotypes, we must understand how neutralizing antibodies target the capsid surface at the molecular level. Here, we report the structures of the human astrovirus capsid spike domain bound to two neutralizing monoclonal antibodies. These antibodies bind two distinct conformational epitopes on the spike surface. We add to existing evidence that the human astrovirus capsid spike contains a receptor-binding domain and demonstrate that both antibodies neutralize human astrovirus by blocking virus attachment to host cells. We identify patches of conserved amino acids which overlap or border the antibody epitopes and may constitute a receptor-binding site. Our findings provide a basis for developing therapies to prevent and treat human astrovirus gastroenteritis.
Human astroviruses infect nearly every person in the world during childhood and cause diarrhea, vomiting, and fever. Despite the prevalence of this virus, little is known about how antibodies block astrovirus infection. Here, we determined the crystal structures of the astrovirus capsid protein in complex with two virus-neutralizing antibodies. We show that the antibodies bind to two distinct sites on the capsid spike domain, however, both antibodies block virus attachment to human cells. Importantly, our findings support the use of the human astrovirus capsid spike as an antigen in a subunit-based vaccine to prevent astrovirus disease.