Three positively charged binding sites on the eastern equine encephalitis virus E2 glycoprotein coordinate heparan sulfate- and protein receptor-dependent infection
Abstract Naturally circulating strains of eastern equine encephalitis virus (EEEV) bind heparan sulfate (HS) receptors and this interaction has been linked to neurovirulence. Previous studies associated EEEV-HS interactions with three positively charged amino acid clusters on the E2 glycoprotein. On...
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| Format: | Article |
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Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62513-3 |
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| author | Maria D. H. Alcorn Chengqun Sun Theron C. Gilliland Tetyana Lukash Christine M. Crasto Saravanan Raju Michael S. Diamond Scott C. Weaver William B. Klimstra |
| author_facet | Maria D. H. Alcorn Chengqun Sun Theron C. Gilliland Tetyana Lukash Christine M. Crasto Saravanan Raju Michael S. Diamond Scott C. Weaver William B. Klimstra |
| author_sort | Maria D. H. Alcorn |
| collection | DOAJ |
| description | Abstract Naturally circulating strains of eastern equine encephalitis virus (EEEV) bind heparan sulfate (HS) receptors and this interaction has been linked to neurovirulence. Previous studies associated EEEV-HS interactions with three positively charged amino acid clusters on the E2 glycoprotein. One of these sites has recently been reported to be critical for binding EEEV to the very-low-density lipoprotein receptor (VLDLR), an EEEV receptor protein. The proteins apolipoprotein E receptor 2 (ApoER2) isoforms 1 and 2, and LDLR have also been shown to function as EEEV receptors. Herein, we investigate the individual contribution of each HS interaction site to EEEV HS- and protein receptor-dependent infection in vitro and EEEV replication in animals. We show that each site contributes to both EEEV-HS and EEEV-protein receptor interactions, providing evidence that altering these interactions can affect disease in mice and eliminate mosquito infectivity. Thus, multiple HS-binding sites exist in EEEV E2, and these sites overlap functionally with protein receptor interaction sites, with each type of interaction contributing to tissue infectivity and disease phenotypes. |
| format | Article |
| id | doaj-art-67c8ce94d75f45f1a693b61e2b3f5638 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-67c8ce94d75f45f1a693b61e2b3f56382025-08-20T04:03:02ZengNature PortfolioNature Communications2041-17232025-08-0116111710.1038/s41467-025-62513-3Three positively charged binding sites on the eastern equine encephalitis virus E2 glycoprotein coordinate heparan sulfate- and protein receptor-dependent infectionMaria D. H. Alcorn0Chengqun Sun1Theron C. Gilliland2Tetyana Lukash3Christine M. Crasto4Saravanan Raju5Michael S. Diamond6Scott C. Weaver7William B. Klimstra8Department of Immunology, University of PittsburghCenter for Vaccine Research, University of PittsburghCenter for Vaccine Research, University of PittsburghDepartment of Immunology, University of PittsburghCenter for Vaccine Research, University of PittsburghDepartment of Medicine, Washington University in St. LouisDepartment of Medicine, Washington University in St. LouisInstitute for Human Infections and Immunity and Department of Microbiology and Immunology, University of Texas Medical BranchDepartment of Immunology, University of PittsburghAbstract Naturally circulating strains of eastern equine encephalitis virus (EEEV) bind heparan sulfate (HS) receptors and this interaction has been linked to neurovirulence. Previous studies associated EEEV-HS interactions with three positively charged amino acid clusters on the E2 glycoprotein. One of these sites has recently been reported to be critical for binding EEEV to the very-low-density lipoprotein receptor (VLDLR), an EEEV receptor protein. The proteins apolipoprotein E receptor 2 (ApoER2) isoforms 1 and 2, and LDLR have also been shown to function as EEEV receptors. Herein, we investigate the individual contribution of each HS interaction site to EEEV HS- and protein receptor-dependent infection in vitro and EEEV replication in animals. We show that each site contributes to both EEEV-HS and EEEV-protein receptor interactions, providing evidence that altering these interactions can affect disease in mice and eliminate mosquito infectivity. Thus, multiple HS-binding sites exist in EEEV E2, and these sites overlap functionally with protein receptor interaction sites, with each type of interaction contributing to tissue infectivity and disease phenotypes.https://doi.org/10.1038/s41467-025-62513-3 |
| spellingShingle | Maria D. H. Alcorn Chengqun Sun Theron C. Gilliland Tetyana Lukash Christine M. Crasto Saravanan Raju Michael S. Diamond Scott C. Weaver William B. Klimstra Three positively charged binding sites on the eastern equine encephalitis virus E2 glycoprotein coordinate heparan sulfate- and protein receptor-dependent infection Nature Communications |
| title | Three positively charged binding sites on the eastern equine encephalitis virus E2 glycoprotein coordinate heparan sulfate- and protein receptor-dependent infection |
| title_full | Three positively charged binding sites on the eastern equine encephalitis virus E2 glycoprotein coordinate heparan sulfate- and protein receptor-dependent infection |
| title_fullStr | Three positively charged binding sites on the eastern equine encephalitis virus E2 glycoprotein coordinate heparan sulfate- and protein receptor-dependent infection |
| title_full_unstemmed | Three positively charged binding sites on the eastern equine encephalitis virus E2 glycoprotein coordinate heparan sulfate- and protein receptor-dependent infection |
| title_short | Three positively charged binding sites on the eastern equine encephalitis virus E2 glycoprotein coordinate heparan sulfate- and protein receptor-dependent infection |
| title_sort | three positively charged binding sites on the eastern equine encephalitis virus e2 glycoprotein coordinate heparan sulfate and protein receptor dependent infection |
| url | https://doi.org/10.1038/s41467-025-62513-3 |
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