Characterization of Attenuated Mutants of MHV3 : Importance of the E2 Protein in Organ Tropism and Infection of Isolated Liver Cells

Martín, J. P.; Chen, W.; Obert, G.; Koehren, F.

doi:10.1007/978-1-4684-5823-7_55

Cited by 6 publications

(7 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We have previously observed that both MHV-A59 (19) and a very weakly hepatotropic strain (C12) (unpublished results) replicate to very similar low titers, suggesting that the hepatocytes are not a major site of replication for MHV-A59. By comparing the highly hepatotropic MHV-3 with MHV-4, it has been also demonstrated that replication in hepatic endothelial cells but not hepatocytes correlated with hepatotropism (22,34,37,38). Our data are consistent with the notion that all three strains may infect the vessel cells but that replication and/or spread from these cells into hepatocytes might be much less efficient with MHV-4.…”

supporting

confidence: 87%

Murine Coronavirus Spike Protein Determines the Ability of the Virus To Replicate in the Liver and Cause Hepatitis

Navas¹,

Seo²,

Chua³

et al. 2001

J Virol

View full text Add to dashboard Cite

Recombinant mouse hepatitis viruses (MHV) differing only in the spike gene, containing A59, MHV-4, and MHV-2 spike genes in the background of the A59 genome, were compared for their ability to replicate in the liver and induce hepatitis in weanling C57BL/6 mice infected with 500 PFU of each virus by intrahepatic injection. Penn98-1, expressing the MHV-2 spike gene, replicated to high titer in the liver, similar to MHV-2, and induced severe hepatitis with extensive hepatocellular necrosis. S A59 R13, expressing the A59 spike gene, replicated to a somewhat lower titer and induced moderate to severe hepatitis with zonal necrosis, similar to MHV-A59. S 4 R21, expressing the MHV-4 spike gene, replicated to a minimal extent and induced few if any pathological changes, similar to MHV-4. Thus, the extent of replication and the degree of hepatitis in the liver induced by these recombinant viruses were determined largely by the spike protein.Various strains of mouse hepatitis virus (MHV) induce different patterns of pathogenesis, including enteritis, hepatitis, encephalitis, and demyelination in the mouse (20,21). We are considering three strains here, MHV-A59, MHV-2, and MHV-4 (an isolate of MHV-JHM). The MHV-A59 strain is dualtropic, producing moderate to severe hepatitis as well as mild to moderate acute meningoencephalitis and chronic demyelination in C57BL/6 weanling mice (29, 30). The MHV-4 strain causes severe acute encephalitis, chronic demyelination, and only minimal levels of hepatitis (6, 23). The MHV-2 strain causes severe hepatitis and meningitis but is unable to cause encephalitis (7,20,42). There are previous studies demonstrating a relationship between attenuation of neurovirulence (6, 10, 13, 42) or hepatitis (14, 28) and the presence of mutations and variations in the spike (S) gene. The S protein, found on the virion envelope and on the plasma membrane of infected cells, is responsible for attachment to viral receptor and viruscell fusion during viral entry and for cell-to-cell fusion later during infection. S is a 180-kDa glycoprotein, which (in the case of most MHV spike proteins) is cleaved into two noncovalently associated 90-kDa subunits, the amino-terminal S1 and carboxy-terminal S2 subunits (14,33). It is speculated that the S1 subunit forms the globular head of the spike and the S2 subunit forms the membrane-bound stalk (8). Recently, a receptor-binding activity has been demonstrated using a recombinant protein containing the amino-terminal 330 residues of the S1 subunit of MHV-JHM (25, 41). S2 is believed to contain the domain that mediates fusion of viral and cell membranes (5, 8). The MHV-2 spike, while highly homologous in sequence to the spike proteins of other MHV strains, remains uncleaved and does not mediate fusion (44,45).Using targeted recombination technology (11,12,35), we have directly demonstrated that the spike protein is a major determinant of the neuropathogenic properties of MHV (39). When the S gene of MHV-4 was introduced into the background of MHV-A59, the resulting recombi...

show abstract

supporting

confidence: 87%

Murine Coronavirus Spike Protein Determines the Ability of the Virus To Replicate in the Liver and Cause Hepatitis

Navas¹,

Seo²,

Chua³

et al. 2001

J Virol

View full text Add to dashboard Cite

show abstract

“…Our results are consistent with the notion that our MV3 escape mutants display at least one single mutation in a determinant of the S glycoprotein. These mutations could be responsible for impairment in recognition of a cellular receptor by the virus in hepatic cells (Martin et al, 1990), thus hindering its multiplication in the liver and delaying the evolution of the disease.…”

Section: In This Work We Compared the In Vivo And In Vitro Virulencementioning

confidence: 99%

“…We prepared monoclonal antibodies (mAb) for the S glycoprotein and used them to select attenuated MHV3 escape mutants for further investigations into the viral pathogenicity and hepatotropism of MHV3, which produces an acute fulminating hepatitis with extensive necrosis of the liver in susceptible BALB/c mice (Lucchiari et al, 1991;Martin etal., 1988;1990).…”

mentioning

confidence: 99%

The virulence of mouse hepatitis virus 3, as evidenced by permissivity of cultured hepatic cells toward escape mutants

Martín

Chen

Koehren

et al. 1994

Research in Virology

Self Cite

View full text Add to dashboard Cite

“…The mAb were chosen to select escape mutants retaining partial pathogenic property. These mAb were able to neutralize MHV3 and to slightly inhibit cellular fusion, but did not protect the sensitive mice against MHV3 infection (Martin et al, 1990). All viruses were cultured in L2 cells.…”

Section: Virusesmentioning

confidence: 99%

“…In contrast, virus-mediated fusion activity is located at a site different from the neutralization epitopes, as shown by the binding sites of several mAb (Collins et al, 1982 ;Routledge et al, 1991). MAb used for the selection of attenuated MHV3 mutants were able to neutralize L2-MHV3 at high dilutions and to slightly inhibit cellular fusion, but did not protect sensitive mice against pathogenic L2-MHV3 infection (Martin et al, 1990), suggesting that these viruses are modified at a site included in a neutralization epitope and located near the fusion site, probably on the S2 portion of the viral glycoprotein (Daniel et al, 1993).…”

Section: Inflammatorymentioning

confidence: 99%

Pathogenicity of neutralization escape mutants of mouse hepatitis virus : correlation with T- and B-cell depletions

Lamontagne

Page

Braunwald

et al. 1994

Research in Immunology

View full text Add to dashboard Cite

Viral pathogenicity is a result of an imbalance between viral replication and the host's immune defences. When the virus is lymphotropic, understanding the pathogenic process of the viral disease becomes complicated because virus/lymphocyte interactions can alter the cell's integrity and subsequently induce immunodeficiency. The immune system plays an important role in the outcome of acute disease induced by the mouse hepatitis virus type 3 (MHV3). The use of attenuated escape mutants provides a tool to study the role of viral properties involved in its pathogenicity. We selected MHV3 mutants by virtue of their resistance to neutralization by monoclonal antibodies (mAb), in order to study their pathogenic properties. We reported that two MHV3 escape mutants were attenuated in their pathogenic properties according to inoculation site and with regard to survival time and ability to deplete T- and B-cell subpopulations in the spleen, thymus and bone marrow of susceptible Balb/c mice. The highly attenuated CL12 mutant could not induce depletion in T or B cells following intraperitoneal (i.p.) or intranasal (i.n.) inoculations, at three days postinfection. The less attenuated 51.6 mutant, however, maintained the ability to deplete T and B cells following i.p. inoculation, as described with the pathogenic MHV3. In contrast, no depletion of T cells following i.n. inoculation was induced with this mutant, although B lineage cells decreased. The use of such mutants enabled us to examine the role of each compartment of the immune system, since the highly attenuated CL12 mutant induced no immunodeficiency, as defined by immune cell depletion, whereas the less attenuated 51.6 mutant maintained its ability to decrease only the B-cell compartment after i.n. inoculation. Results are discussed with regard to the virus/lymphocyte interactions during the pathogenic process.

show abstract

Characterization of Attenuated Mutants of MHV3 : Importance of the E2 Protein in Organ Tropism and Infection of Isolated Liver Cells

Cited by 6 publications

References 10 publications

Murine Coronavirus Spike Protein Determines the Ability of the Virus To Replicate in the Liver and Cause Hepatitis

Murine Coronavirus Spike Protein Determines the Ability of the Virus To Replicate in the Liver and Cause Hepatitis

The virulence of mouse hepatitis virus 3, as evidenced by permissivity of cultured hepatic cells toward escape mutants

Pathogenicity of neutralization escape mutants of mouse hepatitis virus : correlation with T- and B-cell depletions

Contact Info

Product

Resources

About