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

Ricemeyer, Lena; Aguilar-Hernández, Nayeli; López, Tomás; Espinosa, Rafaela; Lanning, Sarah; Mukherjee, Santanu; Cuellar, Carolina; López, Susana; Arias, Carlos F.; DuBois, Rebecca M.

doi:10.1128/jvi.01415-21

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

Journal Article · Wed Oct 06 00:00:00 EDT 2021 · Journal of Virology

DOI:https://doi.org/10.1128/jvi.01415-21· OSTI ID:1861859

^[1]; Aguilar-Hernández, Nayeli ^[2]; López, Tomás ^[2]; Espinosa, Rafaela ^[2]; Lanning, Sarah ^[1]; Mukherjee, Santanu ^[1]; Cuellar, Carolina ^[1]; ^[2]; ^[2]; ^[1]

Univ. of California, Santa Cruz, CA (United States)
Univ. Nacional Autonoma de Mexico (UNAM) (Mexico)

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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC02-05CH11231; AC02-06CH11357

OSTI ID:: 1861859

Journal Information:: Journal of Virology, Journal Name: Journal of Virology Journal Issue: 1 Vol. 96; ISSN 0022-538X

Publisher:: American Society for MicrobiologyCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

References (47)

Astrovirus infection in volunteers Kurtz, J. B.; Lee, T. W.; Craig, J. W. Journal of Medical Virology, Vol. 3, Issue 3 https://doi.org/10.1002/jmv.1890030308	journal	January 1979
An outbreak of gastroenteritis in a home for the elderly associated with astrovirus type 1 and human calicivirus Gray, J. J.; Wreghitt, T. G.; Cubitt, W. D. Journal of Medical Virology, Vol. 23, Issue 4 https://doi.org/10.1002/jmv.1890230410	journal	December 1987
Characterization of a Human Astrovirus Serotype 2 Structural Protein (VP26) That Contains an Epitope Involved in Virus Neutralization Sanchez-Fauquier, A.; Carrascosa, A. L.; Carrascosa, J. L. Virology, Vol. 201, Issue 2 https://doi.org/10.1006/viro.1994.1296	journal	June 1994
Astrovirus gastroenteritis age distribution of antibody Kurtz, John; Lee, Terry Medical Microbiology and Immunology, Vol. 166, Issue 1-4 https://doi.org/10.1007/BF02121154	journal	November 1978
Molecular features of astrovirus associated with a gastroenteritis outbreak in an aged-care centre Marshall, J. A.; Bruggink, L. D.; Sturge, K. European Journal of Clinical Microbiology & Infectious Diseases, Vol. 26, Issue 1 https://doi.org/10.1007/s10096-006-0250-8	journal	January 2007
Outbreaks of astrovirus type 1 and rotavirus gastroenteritis in a geriatric in-patient population Lewis, D. C.; Lightfoot, N. F.; Cubitt, W. D. Journal of Hospital Infection, Vol. 14, Issue 1 https://doi.org/10.1016/0195-6701(89)90128-X	journal	July 1989
Human Astrovirus Serotypes Kurtz, J. B.; Lee, T. W. The Lancet, Vol. 324, Issue 8416 https://doi.org/10.1016/S0140-6736(84)92101-9	journal	December 1984
Viral Causes of Diarrhea Goodgame, Richard W. Gastroenterology Clinics of North America, Vol. 30, Issue 3 https://doi.org/10.1016/S0889-8553(05)70210-7	journal	September 2001
Antiviral activity of ribavirin and favipiravir against human astroviruses Janowski, Andrew B.; Dudley, Holly; Wang, David Journal of Clinical Virology, Vol. 123 https://doi.org/10.1016/j.jcv.2019.104247	journal	February 2020
Immature and Mature Human Astrovirus: Structure, Conformational Changes, and Similarities to Hepatitis E Virus Dryden, Kelly A.; Tihova, Mariana; Nowotny, Norbert Journal of Molecular Biology, Vol. 422, Issue 5 https://doi.org/10.1016/j.jmb.2012.06.029	journal	October 2012
Astrovirus infections in humans and animals – Molecular biology, genetic diversity, and interspecies transmissions De Benedictis, Paola; Schultz-Cherry, Stacey; Burnham, Andrew Infection, Genetics and Evolution, Vol. 11, Issue 7 https://doi.org/10.1016/j.meegid.2011.07.024	journal	October 2011
Astrovirus outbreak at a pediatric hematology and hematopoietic stem cell transplant unit despite strict hygiene rules van der Doef, H. P. J.; Bathoorn, E.; van der Linden, M. P. M. Bone Marrow Transplantation, Vol. 51, Issue 5 https://doi.org/10.1038/bmt.2015.337	journal	January 2016
Fast, scalable generation of high‐quality protein multiple sequence alignments using Clustal Omega Sievers, Fabian; Wilm, Andreas; Dineen, David Molecular Systems Biology, Vol. 7, Issue 1 https://doi.org/10.1038/msb.2011.75	journal	January 2011
Fiji: an open-source platform for biological-image analysis Schindelin, Johannes; Arganda-Carreras, Ignacio; Frise, Erwin Nature Methods, Vol. 9, Issue 7 https://doi.org/10.1038/nmeth.2019	journal	June 2012
Crystal structure of the human astrovirus capsid spike Dong, J.; Dong, L.; Mendez, E. Proceedings of the National Academy of Sciences, Vol. 108, Issue 31 https://doi.org/10.1073/pnas.1104834108	journal	July 2011
RNA sequence of astrovirus: distinctive genomic organization and a putative retrovirus-like ribosomal frameshifting signal that directs the viral replicase synthesis. Jiang, B.; Monroe, S. S.; Koonin, E. V. Proceedings of the National Academy of Sciences, Vol. 90, Issue 22 https://doi.org/10.1073/pnas.90.22.10539	journal	November 1993
Avian astroviruses Koci, Matthew D.; Schultz-Cherry, Stacey Avian Pathology, Vol. 31, Issue 3 https://doi.org/10.1080/03079450220136521	journal	June 2002
A Prospective Case‐Control Study of the Role of Astrovirus in Acute Diarrhea among Hospitalized Young Children Dennehy, Penelope H.; Nelson, Sara M.; Spangenberger, Sara The Journal of Infectious Diseases, Vol. 184, Issue 1 https://doi.org/10.1086/321007	journal	July 2001
Identification of Structural Domains Involved in Astrovirus Capsid Biology Krishna, Neel K. Viral Immunology, Vol. 18, Issue 1 https://doi.org/10.1089/vim.2005.18.17	journal	March 2005
Diagnosis of Neuroinvasive Astrovirus Infection in an Immunocompromised Adult With Encephalitis by Unbiased Next-Generation Sequencing Naccache, Samia N.; Peggs, Karl S.; Mattes, Frank M. Clinical Infectious Diseases, Vol. 60, Issue 6 https://doi.org/10.1093/cid/ciu912	journal	January 2015
Astrovirus VA1/HMO-C: An Increasingly Recognized Neurotropic Pathogen in Immunocompromised Patients Brown, Julianne R.; Morfopoulou, Sofia; Hubb, Jonathan Clinical Infectious Diseases, Vol. 60, Issue 6 https://doi.org/10.1093/cid/ciu940	journal	January 2015
Deciphering key features in protein structures with the new ENDscript server Robert, Xavier; Gouet, Patrice Nucleic Acids Research, Vol. 42, Issue W1 https://doi.org/10.1093/nar/gku316	journal	April 2014
Astrovirus infection in children Walter, Jolan E.; Mitchell, Douglas K. Current Opinion in Infectious Diseases, Vol. 16, Issue 3 https://doi.org/10.1097/00001432-200306000-00011	journal	January 2003
Astrovirus gastroenteritis Mitchell, Douglas K. The Pediatric Infectious Disease Journal, Vol. 21, Issue 11 https://doi.org/10.1097/00006454-200211000-00018	journal	January 2002
Rational Design of Envelope Identifies Broadly Neutralizing Human Monoclonal Antibodies to HIV-1 Wu, X.; Yang, Z. -Y.; Li, Y. Science, Vol. 329, Issue 5993 https://doi.org/10.1126/science.1187659	journal	July 2010
Age-Stratified Seroprevalence of Neutralizing Antibodies to Astrovirus Types 1 to 7 in Humans in The Netherlands Koopmans, M. P. G.; Bijen, M. H. L.; Monroe, S. S. Clinical Diagnostic Laboratory Immunology, Vol. 5, Issue 1 https://doi.org/10.1128/CDLI.5.1.33-37.1998	journal	January 1998
Human Astroviruses Bosch, Albert; Pintó, Rosa M.; Guix, Susana Clinical Microbiology Reviews, Vol. 27, Issue 4 https://doi.org/10.1128/CMR.00013-14	journal	October 2014
Contamination of the Hospital Environment with Gastroenteric Viruses: Comparison of Two Pediatric Wards over a Winter Season Gallimore, Chris I.; Taylor, Clive; Gennery, Andrew R. Journal of Clinical Microbiology, Vol. 46, Issue 9 https://doi.org/10.1128/JCM.00400-08	journal	September 2008
Annual incidence, serotype distribution, and genetic diversity of human astrovirus isolates from hospitalized children in Melbourne, Australia Palombo, E. A.; Bishop, R. F. Journal of Clinical Microbiology, Vol. 34, Issue 7 https://doi.org/10.1128/JCM.34.7.1750-1753.1996	journal	July 1996
Crystal Structure of the Human Astrovirus Capsid Protein Toh, Yukimatsu; Harper, Justin; Dryden, Kelly A. Journal of Virology, Vol. 90, Issue 20 https://doi.org/10.1128/JVI.00694-16	journal	July 2016
Isolation of Neutralizing Monoclonal Antibodies to Human Astrovirus and Characterization of Virus Variants That Escape Neutralization Espinosa, Rafaela; López, Tomás; Bogdanoff, Walter A. Journal of Virology, Vol. 93, Issue 2 https://doi.org/10.1128/JVI.01465-18	journal	October 2018
Astrovirus Replication Is Inhibited by Nitazoxanide In Vitro and In Vivo Hargest, Virginia; Sharp, Bridgett; Livingston, Brandi Journal of Virology, Vol. 94, Issue 5 https://doi.org/10.1128/JVI.01706-19	journal	February 2020
Structure of a Human Astrovirus Capsid-Antibody Complex and Mechanistic Insights into Virus Neutralization Bogdanoff, Walter A.; Campos, Jocelyn; Perez, Edmundo I. Journal of Virology, Vol. 91, Issue 2 https://doi.org/10.1128/JVI.01859-16	journal	November 2016
Structural, Mechanistic, and Antigenic Characterization of the Human Astrovirus Capsid York, Royce L.; Yousefi, Payam A.; Bogdanoff, Walter Journal of Virology, Vol. 90, Issue 5 https://doi.org/10.1128/JVI.02666-15	journal	December 2015
Analysis of astrovirus serotype 1 RNA, identification of the viral RNA-dependent RNA polymerase motif, and expression of a viral structural protein. Lewis, T. L.; Greenberg, H. B.; Herrmann, J. E. Journal of Virology, Vol. 68, Issue 1 https://doi.org/10.1128/JVI.68.1.77-83.1994	journal	January 1994
Characterization of human serotype 1 astrovirus-neutralizing epitopes. Bass, D. M.; Upadhyayula, U. Journal of virology, Vol. 71, Issue 11 https://doi.org/10.1128/JVI.71.11.8666-8671.1997	journal	January 1997
Caspases Mediate Processing of the Capsid Precursor and Cell Release of Human Astroviruses Mendez, E.; Salas-Ocampo, E.; Arias, C. F. Journal of Virology, Vol. 78, Issue 16 https://doi.org/10.1128/JVI.78.16.8601-8608.2004	journal	July 2004
Proteolytic Processing of the Astrovirus Capsid Bass, D. M.; Qiu, S. Journal of Virology, Vol. 74, Issue 4 https://doi.org/10.1128/jvi.74.4.1810-1814.2000	journal	February 2000
Proteolytic Processing of a Serotype 8 Human Astrovirus ORF2 Polyprotein Mendez, E.; Fernandez-Luna, T.; Lopez, S. Journal of Virology, Vol. 76, Issue 16 https://doi.org/10.1128/jvi.76.16.7996-8002.2002	journal	August 2002
Astrovirus Biology and Pathogenesis Cortez, Valerie; Meliopoulos, Victoria A.; Karlsson, Erik A. Annual Review of Virology, Vol. 4, Issue 1 https://doi.org/10.1146/annurev-virology-101416-041742	journal	September 2017
A simplified workflow for monoclonal antibody sequencing Meyer, Lena; López, Tomás; Espinosa, Rafaela PLOS ONE, Vol. 14, Issue 6 https://doi.org/10.1371/journal.pone.0218717	journal	June 2019
Astrovirus Infection and Diarrhea in 8 Countries Olortegui, Maribel Paredes; Rouhani, Saba; Yori, Pablo Peñataro Pediatrics, Vol. 141, Issue 1 https://doi.org/10.1542/peds.2017-1326	journal	January 2018
Food-Related Illness and Death in the United States Mead, Paul S.; Slutsker, Laurence; Dietz, Vance Emerging Infectious Diseases, Vol. 5, Issue 5 https://doi.org/10.3201/eid0505.990502	journal	October 1999
Astrovirus Encephalitis in Boy with X-linked Agammaglobulinemia Quan, Phenix-Lan; Wagner, Thor A.; Briese, Thomas Emerging Infectious Diseases, Vol. 16, Issue 6 https://doi.org/10.3201/eid1606.091536	journal	June 2010
Astrovirus MLB2, a New Gastroenteric Virus Associated with Meningitis and Disseminated Infection Cordey, Samuel; Vu, Diem-Lan; Schibler, Manuel Emerging Infectious Diseases, Vol. 22, Issue 5 https://doi.org/10.3201/eid2205.151807	journal	May 2016
Persistent Infections with Diverse Co-Circulating Astroviruses in Pediatric Oncology Patients, Memphis, Tennessee, USA Cortez, Valerie; Freiden, Pamela; Gu, Zhengming Emerging Infectious Diseases, Vol. 23, Issue 2 https://doi.org/10.3201/eid2302.161436	journal	February 2017
Human Astrovirus 1–8 Seroprevalence Evaluation in a United States Adult Population Meyer, Lena; Delgado-Cunningham, Kevin; Lorig-Roach, Nicholas Viruses, Vol. 13, Issue 6 https://doi.org/10.3390/v13060979	journal	May 2021

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

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