The envelope glycoprotein E2 is a determinant of cell culture tropism in ruminant pestiviruses

Liang, Delin; Sainz, I. Fernández; Ansari, Israrul H.; Gil, Laura Helena Vega Gonzales; Vassilev, Ventzislav; Donis, Ruben O.

doi:10.1099/vir.0.18557-0

Cited by 74 publications

(51 citation statements)

References 29 publications

(17 reference statements)

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“…Partial replacement of the amino terminus of CSFV E2 with the homologous sequence from BVDV resulted in a virus that, although differing from BVDV in its capacity to infect fetal bovine epithelial cells, resembled BVDV with a 10-fold decrease in its ability to replicate in SK6 cells (31). Additionally, a chimeric BVDV containing the complete E2 gene of border disease virus (BDV), similarly to BDV, is unable to replicate in MDBK cells, a cell line permissive for BVDV (16).…”

Section: Discussionmentioning

confidence: 99%

The E2 Glycoprotein of Classical Swine Fever Virus Is a Virulence Determinant in Swine

Risatti

Borca

Kutish

et al. 2005

J Virol

133

108

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To identify genetic determinants of classical swine fever virus (CSFV) virulence and host range, chimeras of the highly pathogenic Brescia strain and the attenuated vaccine strain CS were constructed and evaluated for viral virulence in swine. Upon initial screening, only chimeras 138.8v and 337.14v, the only chimeras containing the E2 glycoprotein of CS, were attenuated in swine despite exhibiting unaltered growth characteristics in primary porcine macrophage cell cultures. Additional viral chimeras were constructed to confirm the role of E2 in virulence. Chimeric virus 319.1v, which contained only the CS E2 glycoprotein in the Brescia background, was markedly attenuated in pigs, exhibiting significantly decreased virus replication in tonsils, a transient viremia, limited generalization of infection, and decreased virus shedding. Chimeras encoding all Brescia structural proteins in a CS genetic background remained attenuated, indicating that additional mutations outside the structural region are important for CS vaccine virus attenuation. These results demonstrate that CS E2 alone is sufficient for attenuating Brescia, indicating a significant role for the CSFV E2 glycoprotein in swine virulence.Classical swine fever (CSF) is a highly contagious and often fatal hemorrhagic disease of swine and is caused by Classical swine fever virus (CSFV), a member of the genus Pestivirus of the family Flaviviridae (5). Intermittent CSF outbreaks in Europe and other parts of the world result in significant economic losses. While infection with highly virulent CSFV strains can cause acute CSF characterized by high morbidity and mortality, isolates of moderate to low virulence induce a prolonged, chronic disease (35).CSFV is a small enveloped virus with a single-stranded, 12.5-kb RNA genome of positive polarity. The CSFV genome contains a single open reading frame encoding an approximately 4,000-amino-acid polyprotein which through cellular and viral protease-mediated co-and posttranslational processing gives rise to the following 11 to 12 final cleavage products: NH 2 -Npro-C-E rns -E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B-COOH (23). Protein C and the glycoproteins E rns , E1, and E2 represent structural components of the virion (28). E1 and E2 are anchored to the envelope by their carboxy termini, with E rns loosely associated with the envelope. E rns and E2 are present as homodimers linked by disulfide bridges on the surfaces of CSFV virions, whereas E2 is also found dimerized with E1 (28, 37, 38). The genetic basis of CSFV virulence and host range remains poorly understood (35).Development of infectious CSFV cDNA clones has enabled genetic approaches for defining mechanisms of viral replication and pathogenesis. Infectious clones (IC) of the attenuated CSFV C-strain and the pathogenic Alfort/Tübingen and Eystrup strains have been constructed, enabling identification of E rns and N pro as virulence factors in swine and of the role of different E rns mutations in virus attenuation (17, 19). Additionally, attempts to mutate and in...

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Section: Discussionmentioning

confidence: 99%

The E2 Glycoprotein of Classical Swine Fever Virus Is a Virulence Determinant in Swine

Risatti

Borca

Kutish

et al. 2005

J Virol

133

108

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“…E2 is the most immunogenic of the CSFV glycoproteins (15,40,44), inducing neutralizing antibodies and protection against lethal CSFV challenge. E2 has been implicated, along with E rns (14) and E1 (43), in viral adsorption to host cells; indeed, chimeric pestiviruses exhibit infectivity and cell tropism phenotypes consistent with those of the E2 gene donor (18,40). Modifications introduced into these glycoproteins appear to have an important effect on CSFV virulence (21,29,31,41).…”

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confidence: 99%

N-Linked Glycosylation Status of Classical Swine Fever Virus Strain Brescia E2 Glycoprotein Influences Virulence in Swine

Risatti

Holinka

Sainz

et al. 2007

J Virol

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E2 is one of the three envelope glycoproteins of classical swine fever virus (CSFV). Previous studies indicate that E2 is involved in several functions, including virus attachment and entry to target cells, production of antibodies, induction of protective immune response in swine, and virulence. Here, we have investigated the role of E2 glycosylation of the highly virulent CSFV strain Brescia in infection of the natural host. Seven putative glycosylation sites in E2 were modified by site-directed mutagenesis of a CSFV Brescia infectious clone (BICv). A panel of virus mutants was obtained and used to investigate whether the removal of putative glycosylation sites in the E2 glycoprotein would affect viral virulence/pathogenesis in swine. We observed that rescue of viable virus was completely impaired by removal of all putative glycosylation sites in E2 but restored when mutation N185A reverted to wild-type asparagine produced viable virus that was attenuated in swine. Single mutations of each of the E2 glycosylation sites showed that amino acid N116 (N1v virus) was responsible for BICv attenuation. N1v efficiently protected swine from challenge with virulent BICv at 3 and 28 days postinfection, suggesting that glycosylation of E2 could be modified for development of classical swine fever live attenuated vaccines.

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“…E2 determines cellular tropism, binds the cell-surface receptor (CD46 or CD81), and contains the major neutralizing antibody epitopes (9,(15)(16)(17)(18). BVDV E2 forms disulfide-linked homodimers and heterodimers with E1 (19)(20)(21).…”

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confidence: 99%

Crystal structure of glycoprotein E2 from bovine viral diarrhea virus

Wang

Kanai

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

112

125

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Pestiviruses, including bovine viral diarrhea virus, are important animal pathogens and are closely related to hepatitis C virus, which remains a major global health threat. They have an outer lipid envelope bearing two glycoproteins, E1 and E2, required for cell entry. They deliver their genome into the host cell cytoplasm by fusion of their envelope with a cellular membrane. The crystal structure of bovine viral diarrhea virus E2 reveals a unique protein architecture consisting of two Ig-like domains followed by an elongated β-stranded domain with a new fold. E2 forms end-to-end homodimers with a conserved C-terminal motif rich in aromatic residues at the contact. A disulfide bond across the interface explains the acid resistance of pestiviruses and their requirement for a redox activation step to initiate fusion. From the structure of E2, we propose alternative possible membrane fusion mechanisms. We expect the pestivirus fusion apparatus to be conserved in hepatitis C virus.domain swap | family Flaviviridae | genus hepacivirus | pH sensing | fusion motif

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The envelope glycoprotein E2 is a determinant of cell culture tropism in ruminant pestiviruses

Cited by 74 publications

References 29 publications

The E2 Glycoprotein of Classical Swine Fever Virus Is a Virulence Determinant in Swine

The E2 Glycoprotein of Classical Swine Fever Virus Is a Virulence Determinant in Swine

N-Linked Glycosylation Status of Classical Swine Fever Virus Strain Brescia E2 Glycoprotein Influences Virulence in Swine

Crystal structure of glycoprotein E2 from bovine viral diarrhea virus

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