Vertebrate-class-specific binding modes of the alphavirus receptor MXRA8

Ofer Zimmerman; Maxwell I Zimmerman; Saravanan Raju; Christopher A Nelson; John M Errico; Emily A Madden; Autumn C Holmes; Ahmed O Hassan; Laura A VanBlargan; Arthur S Kim; Lucas J Adams; Katherine Basore; Bradley M Whitener; Sathvik Palakurty; Hannah G Davis-Adams; Chengqun Sun; Theron Gilliland Jr; James T Earnest; Hongming Ma; Gregory D Ebel; Christian Zmasek; Richard H Scheuermann; William B Klimstra; Daved H Fremont; Michael S Diamond

doi:10.1016/j.cell.2023.09.007

Vertebrate-class-specific binding modes of the alphavirus receptor MXRA8

Cell. 2023 Oct 26;186(22):4818-4833.e25. doi: 10.1016/j.cell.2023.09.007. Epub 2023 Oct 6.

Authors

Ofer Zimmerman¹, Maxwell I Zimmerman², Saravanan Raju², Christopher A Nelson², John M Errico², Emily A Madden¹, Autumn C Holmes¹, Ahmed O Hassan¹, Laura A VanBlargan¹, Arthur S Kim³, Lucas J Adams², Katherine Basore², Bradley M Whitener¹, Sathvik Palakurty¹, Hannah G Davis-Adams¹, Chengqun Sun⁴, Theron Gilliland Jr⁴, James T Earnest¹, Hongming Ma¹, Gregory D Ebel⁵, Christian Zmasek⁶, Richard H Scheuermann⁷, William B Klimstra⁴, Daved H Fremont⁸, Michael S Diamond⁹

Affiliations

¹ Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA.
² Department of Pathology & Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
³ Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Pathology & Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
⁴ Center for Vaccine Research, Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
⁵ Center for Vector-borne Infectious Diseases, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523, USA.
⁶ J. Craig Venter Research Institute, La Jolla, CA 92037, USA.
⁷ J. Craig Venter Research Institute, La Jolla, CA 92037, USA; Department of Pathology, University of California, San Diego, San Diego, CA 92161, USA; Division of Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA, USA; Global Virus Network, Baltimore, MD 92037, USA.
⁸ Department of Pathology & Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, Saint Louis, MO 63110, USA. Electronic address: fremont@wustl.edu.
⁹ Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Pathology & Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Molecular Microbiology, 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. Electronic address: mdiamond@wustl.edu.

Abstract

MXRA8 is a receptor for chikungunya (CHIKV) and other arthritogenic alphaviruses with mammalian hosts. However, mammalian MXRA8 does not bind to alphaviruses that infect humans and have avian reservoirs. Here, we show that avian, but not mammalian, MXRA8 can act as a receptor for Sindbis, western equine encephalitis (WEEV), and related alphaviruses with avian reservoirs. Structural analysis of duck MXRA8 complexed with WEEV reveals an inverted binding mode compared with mammalian MXRA8 bound to CHIKV. Whereas both domains of mammalian MXRA8 bind CHIKV E1 and E2, only domain 1 of avian MXRA8 engages WEEV E1, and no appreciable contacts are made with WEEV E2. Using these results, we generated a chimeric avian-mammalian MXRA8 decoy-receptor that neutralizes infection of multiple alphaviruses from distinct antigenic groups in vitro and in vivo. Thus, different alphaviruses can bind MXRA8 encoded by different vertebrate classes with distinct engagement modes, which enables development of broad-spectrum inhibitors.

Keywords: alphavirus; birds; cryoelectron microscopy; evolution; inhibitor; mammals; pathogenesis; receptor; species; structure; tropism.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Alphavirus*
Animals
Chikungunya Fever
Chikungunya virus / chemistry
Humans
Mammals
Receptors, Virus / metabolism

Substances

alphavirus receptor
Receptors, Virus

Abstract

Publication types

MeSH terms

Substances

Grants and funding