1887

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Volume 102, Issue 8

Dengue virus 3 genotype I shows natural changes in heparan sulphate binding sites, cell interactions, and neurovirulence in a mouse model No Access

Abstract

Dengue virus (DENV) is the most prevalent pathogen of the family. Due to the considerable increase in DENV incidence and spread, symptoms such as CNS involvement have increased. Heparan sulphate (HS) was the first molecule identified as an adhesion factor for DENV in mammalian cells. Viral phenotypes with different HS interactions are associated with various clinical symptoms, including neurological alterations. Here, using analyses studies, and the mouse model, we characterized two natural circulating DENV3 genotype I (GI) lineage 1 (L1) in Brazil–DENV3 MG-20 (from Minas Gerais) and DENV3 PV_BR (from Rondônia) that present divergent neurovirulent profiles and sensitivity to sulphated molecules. We identified substitutions at the viral envelope (E) in positions 62 and 123 as likely responsible for the differences in neurovirulence. The E62K and E123Q substitutions in DENV3 MG-20 and DENV3 PV_BR, respectively, greatly influenced electrostatic density and heparin docking results. , mice inoculated with DENV3 MG-20 died, but not those infected with DENV3 PV_BR. The clinical symptoms, such as paralysis of the lower limbs and meningoencephalitis, and histopathology, also differed between the inoculated groups. heparin and heparinases assays further demonstrated the biological impact of these substitutions. Other characteristics that have been previously associated with alterations in cell tropism and neurovirulence, such as changes in the size of lysis plaques and differences in cytopathic effects in glioblastoma cells, were also observed.

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Keyword(s): DENV3 Genotype I , heparan sulfate binding sites and neurovirulence
Funding
This study was supported by the:
  • L’Oréal-UNESCO (Award 2017 and 2018)
    • Principle Award Recipient: RafaelaSalgado Ferreira
  • Fundação de Amparo à Pesquisa do Estado de Minas Gerais (Award APQ-00846-20)
    • Principle Award Recipient: ERNAGeessien KROON
  • Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Award 001)
    • Principle Award Recipient: ERNAGeessien KROON
  • Departamento de Ciência e Tecnologia do Ministério da Saúde do Brasil (DECIT)nes
    • Principle Award Recipient: ERNAGeessien KROON
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico (Award 440911/2015 and 2058/2016)
    • Principle Award Recipient: ERNAGeessien KROON
© 2021 The Authors
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2021-08-03
2024-04-25
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Dengue virus 3 genotype I shows natural changes in heparan sulphate binding sites, cell interactions, and neurovirulence in a mouse model
J. Gen. Virol. 102, 001630 (2021); https://doi.org/10.1099/jgv.0.001630
/content/journal/jgv/10.1099/jgv.0.001630
/content/journal/jgv/10.1099/jgv.0.001630
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