アルファウイルス受容体MXRA8の脊椎動物クラス特異的結合様式 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
Cell Published:October 06, 2023
•Avian but not mammalian MXRA8 is an entry receptor for WEE complex alphaviruses
•Mammalian but not avian MXRA8 binds to Semliki Forest complex alphaviruses
•Avian and mammalian MXRA8 bind different alphaviruses in flipped orientations
•A chimeric duck-mouse MXRA8 inhibits alphaviruses from multiple antigenic groups
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.
Mxra8は複数の関節炎発症アルファウイルスの受容体である Mxra8 is a receptor for multiple arthritogenic alphaviruses
Rong Zhang,Arthur S. Kim,Julie M. Fox,Sharmila Nair,Katherine Basore,William B. Klimstra,Rebecca Rimkunas,Rachel H. Fong,Hueylie Lin,Subhajit Poddar,James E. Crowe Jr,Benjamin J. Doranz,Daved H. Fremont & Michael S. Diamond
Nature Published:16 May 2018
Arthritogenic alphaviruses comprise a group of enveloped RNA viruses that are transmitted to humans by mosquitoes and cause debilitating acute and chronic musculoskeletal disease1. The host factors required for alphavirus entry remain poorly characterized2. Here we use a genome-wide CRISPR–Cas9-based screen to identify the cell adhesion molecule Mxra8 as an entry mediator for multiple emerging arthritogenic alphaviruses, including chikungunya, Ross River, Mayaro and O’nyong nyong viruses. Gene editing of mouse Mxra8 or human MXRA8 resulted in reduced levels of viral infection of cells and, reciprocally, ectopic expression of these genes resulted in increased infection. Mxra8 bound directly to chikungunya virus particles and enhanced virus attachment and internalization into cells. Consistent with these findings, Mxra8–Fc fusion protein or anti-Mxra8 monoclonal antibodies blocked chikungunya virus infection in multiple cell types, including primary human synovial fibroblasts, osteoblasts, chondrocytes and skeletal muscle cells. Mutagenesis experiments suggest that Mxra8 binds to a surface-exposed region across the A and B domains of chikungunya virus E2 protein, which are a speculated site of attachment. Finally, administration of the Mxra8–Fc protein or anti-Mxra8 blocking antibodies to mice reduced chikungunya and O’nyong nyong virus infection as well as associated foot swelling. Pharmacological targeting of Mxra8 could form a strategy for mitigating infection and disease by multiple arthritogenic alphaviruses.