Heparan Sulfate Binding Can Contribute to the Neurovirulence of Neuroadapted and Nonneuroadapted Sindbis Viruses

Ryman, Kate D.; Gardner, Christina L.; Burke, Crystal W.; Meier, Kathryn C.; Thompson, Joseph M.; Klimstra, William B.

doi:10.1128/jvi.02494-06

Cited by 79Mosquito-borne diseases and controlViral Infections and VectorsVirology and Viral Diseases

Heparan Sulfate Binding Can Contribute to the Neurovirulence of Neuroadapted and Nonneuroadapted Sindbis Viruses

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Ryman, Kate D., Gardner, Christina L., Burke, Crystal W., Meier, Kathryn C., Thompson, Joseph M., Klimstra, William B.·2007·Journal of Virology

DOI 10.1128/jvi.02494-06PMC PMC1866052

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Abstract

Cell culture-adapted laboratory strains of Sindbis virus (SB) exhibit efficient initial attachment to cell surface heparan sulfate (HS) receptors. In contrast, non-cell-adapted strains, such as the SB consensus sequence virus TR339, interact weakly with HS and cell surfaces. Regardless of their HS binding phenotype, most SB strains do not cause fatal disease in adult mice, whether inoculated subcutaneously (s.c.) or intracranially (i.c.). However, laboratory strains of SB can be rendered neurovirulent for adult mice by introduction of a glutamine (Gln)-to-histidine (His) mutation at position 55 of the E2 envelope glycoprotein. In the current work, we have determined that E2 His 55-containing viruses require a second-site mutation (Glu to Lys) at E2 position 70 that confers efficient HS binding in order to exhibit virulence for adult mice and that virulence is correlated with very high infectivity for many cell types. Furthermore, introduction of E2 Lys 70 or certain other HS-binding mutations alone also increased morbidity and/or mortality over that of TR339 for older mice inoculated i.c. However, all viruses containing single HS-binding mutations were attenuated in s.c. inoculated suckling mice in comparison with TR339. These results suggest that HS binding may attenuate viral disease that is dependent on high-titer viremia; however, efficient cell attachment through HS binding can increase virulence, presumably through enhancing the replication of SB within specific host tissues such as the brain.

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The CRISPR screen was performed in ΔB4galt7 N2a cells lacking GAG/HS biosynthesis to avoid heparan sulfate-mediated attachment.
“Because some alphaviruses can attach to cells via engagement of HS11–13, we performed the screen using mouse Neuro2a (termed N2a hereafter) cells that were edited to lack expression of B4galt7 (Extended Data Fig 1b), an enzyme required for glycosaminoglycan (GAG) and HS biosynthesis.”
From LDLRAD3 is a receptor for Venezuelan equine encephalitis virus (2020) · cites this paper as [11]

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Authors: Ryman, K. D., Gardner, C. L., Burke, C. W., Meier, K. C., Thompson, J. M., & Klimstra, W. B.
Affiliations: Louisiana State University Health Sciences Center Shreveport (US)
University of North Carolina at Chapel Hill (US)
ORCID: Gardner, Christina L.
Burke, Crystal W.
Klimstra, William B.
Venue: Journal of Virology
Publisher: American Society for Microbiology
Published: 2007-04
Volume: 81
Issue: 7
Pages: 3563-3573
ISSN: 0022-538X (ISSN-L)
1098-5514
DOI: 10.1128/jvi.02494-06
PMC: PMC1866052
OpenAlex: W2108667057
Cited by: 79
References: 45
Citations by year: 2026: 4 · 2025: 5 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 5 · 2020: 4 · 2019: 6 · 2018: 5 · 2017: 2 · 2016: 4 · 2015: 3 · 2014: 5 · 2013: 5 · 2012: 1
FWCI: 5.15
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Journal of Virology (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
UNC Libraries
Funders: National Institutes of Health
National Institute of Allergy and Infectious Diseases (R01AI022186, R01 AI 22186-19)
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 › Epidemiology › Virology and Viral Diseases
Keywords: Sindbis virus, heparan sulfate binding, neurovirulence, E2 glycoprotein, cell attachment, viral attenuation, intracranial inoculation, viremia, neural adaptation
MeSH terms: Animals, Cell Line, Female, Genotype, Cricetinae, Heparan Sulfate, Histidine, Mutation, Neurons, Replicon, Sindbis Virus, Time Factors, Virulence, Virus Replication, Survival Rate, Genome, Viral, Alphavirus Infections, Mice

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Heparan Sulfate Binding Can Contribute to the Neurovirulence of Neuroadapted and Nonneuroadapted Sindbis Viruses

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