Altered Pathogenesis of a Mutant of the Murine Coronavirus MHV-A59 Is Associated with a Q159L Amino Acid Substitution in the Spike Protein

Leparc-Goffart, Isabelle; Hingley, Susan T.; Chua, Ming Ming; Jiang, Xinhe; Lavi, Ehud; Weiss, Susan R.

doi:10.1006/viro.1997.8877

Cited by 65 publications

(83 citation statements)

References 34 publications

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“…However, because unattenuated ArkDPI is unique at this codon and no field isolates match ArkDPI at this position, codon 498 is unlikely to be important for virulence. In conjunction with the information that the S1 gene determines tropism of coronaviruses (Wesley et al, 1991;Fazakerley et al, 1992;Hingley et al, 1994;Ballesteros et al, 1997;Baric et al, 1997;Leparc-Goffart et al, 1997, 1998Phillips et al, 1999Phillips et al, , 2002Sánchez et al, 1999;Das Sarma et al, 2000;Casais et al, 2003;Ontiveros et al, 2003;Li et al, 2005), our findings suggests that the S1 protein is an important target for selection of these subpopulations in chickens. The selected populations are identical to each other and the parental ArkDPI isolate but different from the predominant vaccine consensus sequence at nucleotide 2034, which is within the S2 coding region.…”

Section: Discussionmentioning

confidence: 77%

“…In addition, because S1 is responsible for virus attachment to cells, differences in the S1 protein affect the species and tissue tropism of IBV and other coronaviruses. The important role of S1 in determining species, cell, and tissue tropism has been demonstrated for several other coronaviruses, including murine hepatitis virus (Fazakerley et al, 1992;Hingley et al, 1994;Baric et al, 1997;Leparc-Goffart et al, 1997, 1998Phillips et al, 1999Phillips et al, , 2002Das Sarma et al, 2000;Ontiveros et al, 2003), porcine transmissible gastroenteritis virus (Wesley et al, 1991;Ballesteros et al, 1997;Sánchez et al, 1999), and sudden acute respiratory syndrome (SARS) coronavirus (Li et al, 2005). In the case of IBV, Casais et al (2003) used a recombinant virus containing mostly the genome of a Vero cell (a Rhesus monkey kidney cell line)-adapted IBV strain and the S1 gene of a chick kidney cell line-adapted strain to demonstrate that the IBV S1 gene is a major determinant of cell tropism in culture.…”

Section: Introductionmentioning

confidence: 99%

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Rapid selection in chickens of subpopulations within ArkDPI-derived infectious bronchitis virus vaccines

Santen

Toro

2008

Avian Pathology

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We examined spike (S) gene sequences of the virus populations of four different commercial ArkDPI-derived infectious bronchitis coronavirus vaccines before and during a single passage in specific pathogen free chickens. We found different degrees of genetic heterogeneity among the four vaccines before passage in chickens, ranging from no apparent heterogeneity to heterogeneity in 20 positions in the S gene. In all except one position, nucleotide differences were non-synonymous. The majority of amino acid differences were in the S1 subunit of the protein. For three of the four ArkDPI-derived vaccines, a single subpopulation with an S gene sequence distinct from the vaccine majority consensus at 5 to 11 codons was selected in chickens within 3 days after ocular vaccination. In contrast, we obtained no evidence for selection of specific subpopulations of the fourth ArkDPI-derived vaccine or Massachusetts or DE072 serotype vaccines. The virus subpopulations within each vaccine selected by chickens are similar in their S1 gene sequences, but distinct in the 3? portion of the S2 subunit gene for each of the three vaccines. In the S1 gene, the selected subpopulations are more similar to the virulent parental ArkDPI isolate than to the predominant vaccine population. The different proportions of distinct subpopulations in Ark vaccines apparently more fit for replication in the respiratory tract of chickens might cause different degrees of damage to respiratory epithelium and/or immune responses in vaccinated chickens. Sequence comparisons provided no evidence to support that ArkDPI-like field isolates were derived directly from host-selected vaccine virus subpopulations.

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Section: Discussionmentioning

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Rapid selection in chickens of subpopulations within ArkDPI-derived infectious bronchitis virus vaccines

Santen

Toro

2008

Avian Pathology

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“…This result may reflect a higher Ag load and increased rate of activation-induced cell death of T cells. Alternately, it may reflect lethal effects of demyelination, as demyelination has been observed to increase with increasing infectious doses (27).…”

Section: Infectious Mhv-a59 Persists In the Cns But Not The Liver Imentioning

confidence: 99%

Antibody Is Required for Clearance of Infectious Murine Hepatitis Virus A59 from the Central Nervous System, But Not the Liver

Matthews

Weiss

Shlomchik

et al. 2001

The Journal of Immunology

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Intracerebral inoculation with mouse hepatitis virus strain A59 results in viral replication in the CNS and liver. To investigate whether B cells are important for controlling mouse hepatitis virus strain A59 infection, we infected muMT mice who lack membrane-bound IgM and therefore mature B lymphocytes. Infectious virus peaked and was cleared from the livers of muMT and wild-type mice. However, while virus was cleared from the CNS of wild-type mice, virus persisted in the CNS of muMT mice. To determine how B cells mediate viral clearance, we first assessed CD4+ T cell activation in the absence of B cells as APC. CD4+ T cells express wild-type levels of CD69 after infection in muMT mice. IFN-γ production in response to viral Ag in muMT mice was also normal during acute infection, but was decreased 31 days postinfection compared with that in wild-type mice. The role of Ab in viral clearance was also assessed. In wild-type mice plasma cells appeared in the CNS around the time that virus is cleared. The muMT mice that received A59-specific Ab had decreased virus, while mice with B cells deficient in Ab secretion did not clear virus from the CNS. Viral persistence was not detected in FcR or complement knockout mice. These data suggest that clearance of infectious mouse hepatitis virus strain A59 from the CNS requires Ab production and perhaps B cell support of T cells; however, virus is cleared from the liver without the involvement of Abs or B cells.

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“…The A59 and JHM strains of the murine member of the coronaviruses (mouse hepatitis virus [MHV]) produce demyelination in mice that mimics many of the pathologic features of MS (12,15,26,39,42,46,47). Chronic MHV-induced demyelination is immune mediated (11, 45), may be partially T-cell dependent (8), and is associated with viral persistence (25, 39) and concomitant enhancement of major histocompatibility complex class I antigens and RNA (9,31,32,43,44).However, many aspects of the mechanism of MHV-induced demyelination are still unknown.Various biologic properties of MHV are associated with the viral envelope spike (S) glycoprotein (3,4,6,10,16,35,40). However, demyelination determinants in MHV have never been directly localized to any specific viral protein or gene.…”

mentioning

confidence: 99%

“…Various biologic properties of MHV are associated with the viral envelope spike (S) glycoprotein (3,4,6,10,16,35,40). However, demyelination determinants in MHV have never been directly localized to any specific viral protein or gene.…”

mentioning

confidence: 99%

Demyelination Determinants Map to the Spike Glycoprotein Gene of Coronavirus Mouse Hepatitis Virus

Sarma¹,

Fu²,

Tsai

et al. 2000

J Virol

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150

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Demyelination is the pathologic hallmark of the human immune-mediated neurologic disease multiple sclerosis, which may be triggered or exacerbated by viral infections. Several experimental animal models have been developed to study the mechanism of virus-induced demyelination, including coronavirus mouse hepatitis virus (MHV) infection in mice. The envelope spike (S) glycoprotein of MHV contains determinants of properties essential for virus-host interactions. However, the molecular determinants of MHV-induced demyelination are still unknown. To investigate the mechanism of MHV-induced demyelination, we examined whether the S gene of MHV contains determinants of demyelination and whether demyelination is linked to viral persistence. Using targeted RNA recombination, we replaced the S gene of a demyelinating virus (MHV-A59) with the S gene of a closely related, nondemyelinating virus (MHV-2). Recombinant viruses containing an S gene derived from MHV-2 in an MHV-A59 background (Penn98-1 and Penn98-2) exhibited a persistence-positive, demyelination-negative phenotype. Thus, determinants of demyelination map to the S gene of MHV. Furthermore, viral persistence is insufficient to induce demyelination, although it may be a prerequisite for the development of demyelination.Primary demyelination is a pathologic process in which myelin is destroyed, while neuronal axons remain relatively preserved. The demyelinating process can occur by either a direct attack on oligodendrocytes, the cells that produce and maintain myelin, or an autoimmune attack against myelin components, resulting in secondary destruction of oligodendrocytes. The most prevalent primary demyelinating disease in humans is multiple sclerosis (MS), which affects over a quarter of a million individuals in the United States (2). The etiology and pathogenesis of MS have long been investigated; however, causation has not been proven. There is a consensus that the process involves a T-cell-mediated autoimmune phenomenon that may be triggered by one or more viral infections (1). Several experimental animal models have been developed in order to better understand the mechanism of demyelination. Experimental autoimmune encephalomyelitis and several virus-induced experimental models, including coronavirus infection in mice (5), have been instrumental in providing insight into the pathogenesis of demyelination.Coronaviruses, members of the order Nidovirales, form a group of enveloped single-stranded RNA viruses (22,33,36,46). Many members of the nidoviruses, including coronaviruses and arteriviruses, infect the central nervous system and provide experimental animal model systems for neurologic diseases (30). The A59 and JHM strains of the murine member of the coronaviruses (mouse hepatitis virus [MHV]) produce demyelination in mice that mimics many of the pathologic features of MS (12,15,26,39,42,46,47). Chronic MHV-induced demyelination is immune mediated (11, 45), may be partially T-cell dependent (8), and is associated with viral persistence (25, 39) and concomit...

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Altered Pathogenesis of a Mutant of the Murine Coronavirus MHV-A59 Is Associated with a Q159L Amino Acid Substitution in the Spike Protein

Cited by 65 publications

References 34 publications

Rapid selection in chickens of subpopulations within ArkDPI-derived infectious bronchitis virus vaccines

Rapid selection in chickens of subpopulations within ArkDPI-derived infectious bronchitis virus vaccines

Antibody Is Required for Clearance of Infectious Murine Hepatitis Virus A59 from the Central Nervous System, But Not the Liver

Demyelination Determinants Map to the Spike Glycoprotein Gene of Coronavirus Mouse Hepatitis Virus

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