アルファウイルス感染を阻止する方法を特定(Researchers identify way to block alphavirus infection)

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2023-11-27 ワシントン大学セントルイス校

◆ワシントン大学医学部の研究者は、アルファウイルスと呼ばれる蚊媒介のウイルスの感染を阻止するための新しい方法を見つけました。これらのウイルスは関節や脳の感染を引き起こす可能性があり、特に抗ウイルス薬がないため深刻な問題です。
◆研究では、関節炎を引き起こすウイルスがMXRA8と呼ばれる分子に依存して人間の細胞に侵入することが分かりました。更に、鳥のMXRA8にのみ結合し、この特性を利用してウイルスに対抗するための合成分子を作成し、マウスでの感染を防ぐことに成功しました。この研究は、広範な治療法への第一歩となり、アルファウイルス感染に対する画期的なアプローチを提供しています。

<関連情報>

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
DOI:https://doi.org/10.1016/j.cell.2023.09.007

Highlights

•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

Summary

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.

Graphical abstract

Figure thumbnail fx1

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
DOI:https://doi.org/10.1038/s41586-018-0121-3

extended data figure 1

Abstract

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.

 

 

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