ArticleProceedings of the National Academy of Sciences of the United States of America2011
Heparan sulfate binding by natural eastern equine encephalitis viruses promotes neurovirulence.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 98 papers, 1 of them a synthesis that pooled it.
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Who cites it
98 citing papers in PubMed, 1 synthesis or guideline pooled it, 140 citations in OpenAlex.
- The life cycle of the alphaviruses: From an antiviral perspective.Antiviral research · 2023Pooled it
- Spatial dynamics of viral replication drive biphasic lymphoid activation and systemic alphavirus immune responses.PLoS pathogens · 2026Article
- Clinical dose of enoxaparin enhances oncolytic virus M1 infection and antitumor efficacy in human bladder cancer.iScience · 2026Article
- The residue 86 of the Getah virus E2 glycoprotein mediates both glycosaminoglycan- and LDLR-dependent infection.PLoS pathogens · 2026Article
- Review
- LRP4 is an entry receptor for multiple encephalitic alphaviruses.Nature communications · 2026Article
- Informed mutation of western equine encephalitis virus to heparan sulfate binding: Implications for rational design of alphavirus live attenuated vaccines.PLoS pathogens · 2026Article
- Glycosylation of GETV E2 promotes pathogenesis in animal models.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Meta-analysis of functional genomics studies reveals conserved cellular pathways required by viruses of pandemic concern.Access microbiology · 2026Article
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- An inactivated trivalent virion-based vaccine protects against aerosol challenge with encephalitic alphaviruses in mice and macaques.Science translational medicine · 2025Article
- Structural elucidation of a unique binding mode by an intact alphavirus human IgG molecule to a quaternary epitope.Nature communications · 2025Article
- Three positively charged binding sites on the eastern equine encephalitis virus E2 glycoprotein coordinate heparan sulfate- and protein receptor-dependent infection.Nature communications · 2025Article
- Review
- Basic patches on the E2 glycoprotein of eastern equine encephalitis virus influence viral vascular clearance and dissemination in mice.Journal of virology · 2025Article
- A detailed kinetic model of Eastern equine encephalitis virus replication in a susceptible host cell.PLoS computational biology · 2025Article
- Article
- Infectomics of Chikungunya Virus: Roles Played by Host Factors.The American journal of tropical medicine and hygiene · 2025Review
- Antiviral efficacy of heparan sulfate and enoxaparin sodium against SARS-CoV-2.Archiv der Pharmazie · 2025Article
38 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
The Alphavirus genus of the family Togaviridae contains mosquito-vectored viruses that primarily cause either arthritogenic disease or acute encephalitis. North American eastern equine encephalitis virus (NA-EEEV) is uniquely neurovirulent among encephalitic alphaviruses, causing mortality in a majority of symptomatic cases and neurological sequelae in many survivors. Unlike many alphaviruses, NA-EEEV infection of mice yields limited signs of febrile illness typically associated with lymphoid tissue replication. Rather, signs of brain infection, including seizures, are prominent. Use of heparan sulfate (HS) as an attachment receptor increases the neurovirulence of cell culture-adapted strains of Sindbis virus, an arthritogenic alphavirus. However, this receptor is not known to be used by naturally circulating alphaviruses. We demonstrate that wild-type NA-EEEV strain FL91-4679 uses HS as an attachment receptor and that the amino acid sequence of its E2 attachment protein is identical to those of natural isolates sequenced by RT-PCR amplification of field samples. This finding unequivocally confirms the use of HS receptors by naturally circulating NA-EEEV strains. Inactivation of the major HS binding domain in NA-EEEV E2 demonstrated that the HS binding increased brain replication and neurologic disease but reduced lymphoid tissue replication, febrile illness signs, and cytokine/chemokine induction in mice. We propose that HS binding by natural NA-EEEV strains alters tropism in vivo to antagonize/evade immune responses, and the extreme neurovirulence of wild-type NA-EEEV may be a consequence. Therefore, reinvestigation of HS binding by this and other arboviruses is warranted.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.