Heparan Sulfate-Independent Infection Attenuates High-Neurovirulence GDVII Virus-Induced Encephalitis

Reddi, Honey V.; Kumar, Anil; Kung, Aisha Y.; Kallio, Patricia; Schlitt, Brian P.; Lipton, Howard L.

doi:10.1128/jvi.78.16.8909-8916.2004

Cited by 16 publications

(14 citation statements)

References 42 publications

(33 reference statements)

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“…This finding suggests that EV-71-heparin interactions involve mainly electrostatic charge interactions. Replacement of a single positively charged amino acid with another amino acid is sufficient to retard the heparin binding phenotype in TMEV GDVII and coxsackievirus A9 (27,34,60). Thus, positively charged amino acids on the surfaces of viral particles are critical for the heparin binding phenotype.…”

Section: Discussionmentioning

confidence: 99%

Enterovirus 71 Uses Cell Surface Heparan Sulfate Glycosaminoglycan as an Attachment Receptor

Tan

Poh

Sam

et al. 2013

J Virol

169

183

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Section: Discussionmentioning

confidence: 99%

Enterovirus 71 Uses Cell Surface Heparan Sulfate Glycosaminoglycan as an Attachment Receptor

Tan

Poh

Sam

et al. 2013

J Virol

169

183

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“…We have recently demonstrated a similar phenomenon in the C-type lectin receptor usage of mosquito cell- These results promote the idea that HS-binding mutants with increased cell infectivities could arise during the replication cycle of an alphavirus within a single vertebrate host, perhaps exacerbating damage to particular tissues later in infection. HS binding contributes to the severity of encephalitis after infection with Theiler's murine encephalomyelitis virus (35). The fact that RNA viruses exist as rapidly adaptable quasispecies (7) makes this idea even more appealing.…”

Section: Discussionmentioning

confidence: 99%

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

Ryman

Gardner

Burke

et al. 2007

J Virol

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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 HSbinding 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.Sindbis virus (SB) strain AR339 is considered the prototypic virus of the Alphavirus genus, family Togaviridae. This family of mosquito-borne RNA viruses includes several significant human pathogens and potential bioterrorism or biowarfare agents such as Venezuelan and Eastern equine encephalitis viruses (VEEV and EEEV, respectively) (3, 44). Consequently, there has been a resurgence of interest in characterizing the molecular determinants of alphavirus neurovirulence. Due to the relative difficulty and risk of handling the more pathogenic alphaviruses, SB has been used extensively as a model system for the study of the alphavirus replication cycle and the pathogenesis of disease (reviewed in reference 16).Many laboratory strains descended from SB AR339 initially attach to cells through interaction with heparan sulfate (HS), a negatively charged glycosaminoglycan (GAG) found on the surfaces of most cells (4,26). This also appears to be the case with cell culture-adapted laboratory strains of other alphaviruses (1, 18, 39). However, in contrast to laboratory strains, virus particles derived from a cDNA clone representing a consensus sequence of SB group viruses (strain TR339) (32) do not attach efficiently to HS or cell surfaces (26). Furthermore, the cell attachment phenotype of TR339 is indistinguishable from that of a virus generated from a cDNA clone of an ancestral SB AR339 preserved prior to adaptation for growth in cultured cells (W. B. Klimstra, D. E. Deming, R. E. Johnston, and K. D. Ryman, unpublished observat...

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“…7C) [41]. GD-A745 no longer used HS for binding and entry, and infectious virus yields in mammalian cells were 25-fold higher for the adapted virus compared to the parental GDVII virus in BHK-21 cells [41].…”

Section: Gdvii Hs Co-receptor Use Influences Range Of Neuronal Infectmentioning

confidence: 99%

“…GD-A745 no longer used HS for binding and entry, and infectious virus yields in mammalian cells were 25-fold higher for the adapted virus compared to the parental GDVII virus in BHK-21 cells [41]. Disease pathogenesis was analyzed in 5-to 6-week-old CD-1 mice inoculated ic with 100 pfu of GDVII or GD-A745 viruses [41].…”

Section: Gdvii Hs Co-receptor Use Influences Range Of Neuronal Infectmentioning

confidence: 99%

“…The interaction between high-neurovirulence TMEV and its co-receptor was further studied using GDVII virus adapted to PG-deficient cells [41]. To generate a high-neurovirulence TMEV that did not require binding to HS, GDVII virus was passed in CHO mutant pgsA-745 cells deficient in xylosyl transferase [42], an enzyme required for attachment of the tetrasaccharide linker to the protein core and for GAG synthesis.…”

Section: Gdvii Hs Co-receptor Use Influences Range Of Neuronal Infectmentioning

confidence: 99%

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Differential usage of carbohydrate co-receptors influences cellular tropism of Theiler's murine encephalomyelitis virus infection of the central nervous system

et al. 2006

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Theiler's murine encephalomyelitis viruses (TMEV) are ubiquitous pathogens of mice, producing either rapidly fatal encephalitis (high-neurovirulence strains) or persistent central nervous system infection and inflammatory demyelination (low-neurovirulence strains). Although a protein entry receptor has not yet been identified, carbohydrate co-receptors that effect docking and concentration of the virus on the cell surface are known for both TMEV neurovirulence groups. Low-neurovirulence TMEV use alpha2,3-linked N-acetylneuramic acid (sialic acid) on an N-linked glycoprotein, whereas high-neurovirulence TMEV use the proteoglycan heparan sulfate (HS) as a co-receptor. While the binding of low-neurovirulence TMEV to sialic acid can be inhibited completely, only a third of the binding of high-neurovirulence TMEV to HS is inhibitable, suggesting that high-neurovirulence strains use another co-receptor or bind directly to the putative protein entry receptor. Four amino acids on the surface (VP2 puff B) of low-neurovirulence strains make contact with sialic acid through non-covalent hydrogen bonds. Since these virus residues are conserved in all TMEV strains, the capsid conformation of this region is probably responsible for sialic acid binding. A persistence determinant that maps within the virus coat using recombinant TMEV is also conformational in nature. Low-neurovirulence virus variants that do not bind to sialic acid fail to persist in the central nervous system of mice, indicating a role for sialic acid binding in TMEV persistence. Analysis of high-neurovirulence variants that do not bind HS demonstrates that HS co-receptor usage influences neuronal tropism in brain, whereas, the HS co-receptor use is not required for the infection of spinal cord anterior horn cells associated with poliomyelitis.

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Heparan Sulfate-Independent Infection Attenuates High-Neurovirulence GDVII Virus-Induced Encephalitis

Cited by 16 publications

References 42 publications

Enterovirus 71 Uses Cell Surface Heparan Sulfate Glycosaminoglycan as an Attachment Receptor

Enterovirus 71 Uses Cell Surface Heparan Sulfate Glycosaminoglycan as an Attachment Receptor

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

Differential usage of carbohydrate co-receptors influences cellular tropism of Theiler's murine encephalomyelitis virus infection of the central nervous system

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