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11 11, 2020;28 (5): 699-711.e7.

Human mAbs Broadly Protect against Arthritogenic Alphaviruses by Recognizing Conserved Elements of the Mxra8 Receptor-Binding Site.

Laura A Powell, Andrew Miller, Julie M Fox, Nurgun Kose, Thomas Klose, Arthur S Kim, Robin Bombardi, Rashika N Tennekoon, A Dharshan de Silva, Robert H Carnahan, Michael S Diamond, Michael G Rossmann, Richard J Kuhn, James E Crowe
Author Information
  1. Laura A Powell: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  2. Andrew Miller: Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA.
  3. Julie M Fox: Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA.
  4. Nurgun Kose: Vanderbilt Vaccine Center, Department of Pediatrics, Nashville, TN 37232, USA.
  5. Thomas Klose: Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA.
  6. Arthur S Kim: Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
  7. Robin Bombardi: Vanderbilt Vaccine Center, Department of Pediatrics, Nashville, TN 37232, USA.
  8. Rashika N Tennekoon: Genetech Research Institute, Colombo, Sri Lanka; Department of Paraclinical Sciences, Faculty of Medicine, Kotelawala Defence University, Colombo, Sri Lanka.
  9. A Dharshan de Silva: Genetech Research Institute, Colombo, Sri Lanka; Department of Paraclinical Sciences, Faculty of Medicine, Kotelawala Defence University, Colombo, Sri Lanka.
  10. Robert H Carnahan: Vanderbilt Vaccine Center, Department of Pediatrics, Nashville, TN 37232, USA; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  11. Michael S Diamond: Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA; Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, Saint Louis, MO 63110, USA.
  12. Michael G Rossmann: Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA.
  13. Richard J Kuhn: Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA; Markey Center for Structural Biology and Purdue Institute of Inflammation, Immunology and Infectious Disease, Purdue University, West Lafayette, IN 47907, USA.
  14. James E Crowe: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Vaccine Center, Department of Pediatrics, Nashville, TN 37232, USA; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address: james.crowe@vumc.org.
PMID: 32783883 DOI: 10.1016/j.chom.2020.07.008

Abstract

Mosquito inoculation of humans with arthritogenic alphaviruses results in a febrile syndrome characterized by debilitating musculoskeletal pain and arthritis. Despite an expanding global disease burden, no approved therapies or licensed vaccines exist. Here, we describe human monoclonal antibodies (mAbs) that bind to and neutralize multiple distantly related alphaviruses. These mAbs compete for an antigenic site and prevent attachment to the recently discovered Mxra8 alphavirus receptor. Three cryoelectron microscopy structures of Fab in complex with Ross River (RRV), Mayaro, or chikungunya viruses reveal a conserved footprint of the broadly neutralizing mAb RRV-12 in a region of the E2 glycoprotein B domain. This mAb neutralizes virus in vitro by preventing virus entry and spread and is protective in vivo in mouse models. Thus, the RRV-12 mAb and its defined epitope have potential as a therapeutic agent or target of vaccine design against multiple emerging arthritogenic alphavirus infections.

Keywords

Chikungunya virus Mayaro virus O’nyong’nyong virus Ross River virus alphavirus antibodies arthritis cross-reactivity infectious viral

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Grants

  1. R01 AI095366/NIAID NIH HHS
  2. HHSN272201400018C/NIAID NIH HHS
  3. R01 AI114816/NIAID NIH HHS
  4. R01 AI143673/NIAID NIH HHS
  5. U19 AI142790/NIAID NIH HHS

MeSH Term

Alphavirus
Alphavirus Infections
Animals
Antibodies, Monoclonal
Antibodies, Neutralizing
Antibodies, Viral
Arthritis
Binding Sites
Chikungunya virus
Chlorocebus aethiops
Cross Reactions
Cryoelectron Microscopy
Epitopes
Female
Humans
Immunoglobulins
Male
Membrane Proteins
Mice
Mice, Inbred C57BL
Middle Aged
Receptors, Virus
Ross River virus
Vero Cells
Virus Internalization

Chemicals

Antibodies, Monoclonal
Antibodies, Neutralizing
Antibodies, Viral
Epitopes
Immunoglobulins
Membrane Proteins
Mxra8 protein, mouse
Receptors, Virus
alphavirus receptor
Journal Article Research Support, N.I.H., Extramural

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