Cited by 448Mosquito-borne diseases and controlViral Infections and VectorsSARS-CoV-2 and COVID-19 Research

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Mxra8 is a receptor for multiple arthritogenic alphaviruses

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Zhang, Rong, Kim, Arthur S., Fox, Julie M., Nair, Sharmila, Basore, Katherine, Klimstra, William B., Rimkunas, Rebecca, Fong, Rachel H., Lin, Hueylie, Poddar, Subhajit, Crowe, James E., Doranz, Benjamin J., Fremont, Daved H., Diamond, Michael S.·2018·Nature

DOI 10.1038/s41586-018-0121-3PMC PMC5970976

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Abstract

Arthritogenic alphaviruses comprise a group of enveloped RNA viruses that are transmitted to humans by mosquitoes and cause debilitating acute and chronic musculoskeletal disease 1 . The host factors required for alphavirus entry remain poorly characterized 2 . 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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Additional file 5 of Surfaceome CRISPR screen identifies OLFML3 as a rhinovirus-inducible IFN antagonist
Mei, H., Zha, Z., Wang, W. J., Xie, Y., Huang, Y., Li, W., Wei, D., Zhang, X., Qu, J., & Liu, J. (2021) · Figshare · doi:10.6084/m9.figshare.16862824
Additional file 8 of Surfaceome CRISPR screen identifies OLFML3 as a rhinovirus-inducible IFN antagonist
Mei, H., Zha, Z., Wang, W., Xie, Y., Huang, Y., Li, W., Wei, D., Zhang, X., Qu, J., & Liu, J. (2021) · Figshare · doi:10.6084/m9.figshare.16862836
Additional file 11 of Surfaceome CRISPR screen identifies OLFML3 as a rhinovirus-inducible IFN antagonist
Mei, H., Zha, Z., Wang, W. J., Xie, Y., Huang, Y., Li, W., Wei, D., Zhang, X., Qu, J., & Liu, J. (2021) · Figshare · doi:10.6084/m9.figshare.16862800
Additional file 4 of Surfaceome CRISPR screen identifies OLFML3 as a rhinovirus-inducible IFN antagonist
Mei, H., Zha, Z., Wang, W. J., Xie, Y., Huang, Y., Li, W., Wei, D., Zhang, X., Qu, J., & Liu, J. (2021) · Figshare · doi:10.6084/m9.figshare.16862818
Additional file 12 of Surfaceome CRISPR screen identifies OLFML3 as a rhinovirus-inducible IFN antagonist
Mei, H., Zha, Z., Wang, W., Xie, Y., Huang, Y., Li, W., Wei, D., Zhang, X., Qu, J., & Liu, J. (2021) · Figshare · doi:10.6084/m9.figshare.16862803
Additional file 2 of Highly potent multivalent VHH antibodies against Chikungunya isolated from an alpaca naïve phage display library
Li, Q., Zhang, F., Lu, Y., Hu, H., Wang, J., Guo, C., Deng, Q., Liao, C., Wu, Q., Hu, T., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19767947
Additional file 6 of Surfaceome CRISPR screen identifies OLFML3 as a rhinovirus-inducible IFN antagonist
Mei, H., Zha, Z., Wang, W., Xie, Y., Huang, Y., Li, W., Wei, D., Zhang, X., Qu, J., & Liu, J. (2021) · Figshare · doi:10.6084/m9.figshare.16862827
Additional file 3 of Surfaceome CRISPR screen identifies OLFML3 as a rhinovirus-inducible IFN antagonist
Mei, H., Zha, Z., Wang, W. J., Xie, Y., Huang, Y., Li, W., Wei, D., Zhang, X., Qu, J., & Liu, J. (2021) · Figshare · doi:10.6084/m9.figshare.16862815
Additional file 9 of Surfaceome CRISPR screen identifies OLFML3 as a rhinovirus-inducible IFN antagonist
Mei, H., Zha, Z., Wang, W. J., Xie, Y., Huang, Y., Li, W., Wei, D., Zhang, X., Qu, J., & Liu, J. (2021) · Figshare · doi:10.6084/m9.figshare.16862839
Additional file 10 of Surfaceome CRISPR screen identifies OLFML3 as a rhinovirus-inducible IFN antagonist
Mei, H., Zha, Z., Wang, W. J., Xie, Y., Huang, Y., Li, W., Wei, D., Zhang, X., Qu, J., & Liu, J. (2021) · Figshare · doi:10.6084/m9.figshare.16862797
Additional file 7 of Surfaceome CRISPR screen identifies OLFML3 as a rhinovirus-inducible IFN antagonist
Mei, H., Zha, Z., Wang, W. J., Xie, Y., Huang, Y., Li, W., Wei, D., Zhang, X., Qu, J., & Liu, J. (2021) · Figshare · doi:10.6084/m9.figshare.16862833
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Additional file 2 of Surfaceome CRISPR screen identifies OLFML3 as a rhinovirus-inducible IFN antagonist
Mei, H., Zha, Z., Wang, W., Xie, Y., Huang, Y., Li, W., Wei, D., Zhang, X., Qu, J., & Liu, J. (2021) · Figshare · doi:10.6084/m9.figshare.16862812
Additional file 1 of Attenuation of neurovirulence of chikungunya virus by a single amino acid mutation in viral E2 envelope protein
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Additional file 1 of Surfaceome CRISPR screen identifies OLFML3 as a rhinovirus-inducible IFN antagonist
Mei, H., Zha, Z., Wang, W., Xie, Y., Huang, Y., Li, W., Wei, D., Zhang, X., Qu, J., & Liu, J. (2021) · Figshare · doi:10.6084/m9.figshare.16862809
Additional file 1 of Highly potent multivalent VHH antibodies against Chikungunya isolated from an alpaca naïve phage display library
Li, Q., Zhang, F., Lu, Y., Hu, H., Wang, J., Guo, C., Deng, Q., Liao, C., Wu, Q., Hu, T., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19767944
Additional file 13 of Surfaceome CRISPR screen identifies OLFML3 as a rhinovirus-inducible IFN antagonist
Mei, H., Zha, Z., Wang, W., Xie, Y., Huang, Y., Li, W., Wei, D., Zhang, X., Qu, J., & Liu, J. (2021) · Figshare · doi:10.6084/m9.figshare.16862806
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Authors: Zhang, R., Kim, A. S., Fox, J. M., Nair, S., Basore, K., Klimstra, W. B., Rimkunas, R., Fong, R. H., Lin, H., Poddar, S., Crowe, J. E., Doranz, B. J., Fremont, D. H., & Diamond, M. S.
Affiliations: Washington University in St. Louis (US)
University of Pittsburgh (US)
Integral Molecular (United States) (US)
Vanderbilt University Medical Center (US)
Corresponding author: Diamond, Michael S.
ORCID: Zhang, Rong
Kim, Arthur S.
Fox, Julie M.
Nair, Sharmila
Basore, Katherine
Klimstra, William B.
Fong, Rachel H.
Lin, Hueylie
Poddar, Subhajit
Crowe, James E.
Doranz, Benjamin J.
Fremont, Daved H.
Diamond, Michael S.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2018-05
Volume: 557
Issue: 7706
Pages: 570-574
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/s41586-018-0121-3
PMC: PMC5970976
OpenAlex: W2803841447
Cited by: 448
References: 41
Citations by year: 2026: 60 · 2025: 61 · 2024: 58 · 2023: 54 · 2022: 64 · 2021: 62 · 2020: 47 · 2019: 35 · 2018: 6
FWCI: 38.14
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: National Institute of Allergy and Infectious Diseases (R01AI114816, R01AI123348, R01AI095436)
Topics: Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Mosquito-borne diseases and control
Health Sciences › Medicine › Infectious Diseases › Viral Infections and Vectors
Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
Keywords: MXRA8, arthritogenic alphaviruses, chikungunya virus, Ross River virus, Mayaro virus, O'nyong-nyong virus, viral entry, adhesion molecules, foot swelling, synovial fibroblasts, CRISPR-Cas9 screen
MeSH terms: Animals, Chikungunya virus, Fibroblasts, Humans, Immunoglobulins, Male, Membrane Proteins, Osteoblasts, Receptors, Fc, Receptors, Virus, 3T3 Cells, Muscle, Skeletal, Antibodies, Blocking, Chondrocytes, Mice, CRISPR-Cas Systems, O'nyong-nyong Virus

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Mxra8 is a receptor for multiple arthritogenic alphaviruses

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