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

Abstract

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.

Intrahepatic endothelial and Kupffer cells involved in immunosuppressive cytokines and natural killer (NK)/NK T cell disorders in viral acute hepatitis

“…The livers from YAC-MHV3-infected mice exhibited normal colour and texture. Macroscopic observations were consistent with previous pathological features of the liver from mice infected with these variants, as reported previously [23,25,26].…”

“…We have demonstrated previously that viral replication cannot explain the levels of hepatitis, as similar viral titres were found in livers from mice infected with pathogenic L2‐MHV3, low attenuated 51·6‐MHV3, highly attenuated CL12‐MHV3 or non‐pathogenic YAC‐MHV3 viruses [26,27]. Viral pathogenicity correlates more with the time of appearance of virus titres in liver than the level of viral titres [26]. These observations support the hypothesis that the pathogenicity of the viral variants reflects their ability to trigger the inflammatory response rather than their capacity to replicate.…”

“…The use of attenuated viral variants which have lost their ability to replicate in LSEC and/or KC cells involved in the control of liver tolerance allowed us to evaluate the role for these cells in viral acute hepatitis. We have demonstrated previously that viral replication cannot explain the levels of hepatitis, as similar viral titres were found in livers from mice infected with pathogenic L2‐MHV3, low attenuated 51·6‐MHV3, highly attenuated CL12‐MHV3 or non‐pathogenic YAC‐MHV3 viruses [26,27]. Viral pathogenicity correlates more with the time of appearance of virus titres in liver than the level of viral titres [26].…”

“…Previous histopathological studies have shown that the pathogenic L2‐MHV3 virus induces extensive necrotic foci in liver, whereas few perivascular inflammatory foci are observed transiently in mice infected with the non‐pathogenic YAC‐MHV3 variant [23]. Histopathological studies have revealed dramatic effects in L2‐MHV3‐infected mice for which hepatocellular necrosis in the presence of inflammatory cells was evident in the presence of high transaminase activity in serum [26,34]. Moderate liver necrosis and infiltration of inflammatory cells, however, were seen in both 51·6‐MHV3‐ and CL12‐MHV3‐infected mice in which low and no transaminase activity was detected.…”

“…The highly attenuated CL12-MHV3 variant induces the death of mice within 8-10 days, minor hepatitis with perivascular inflammatory foci, no immunodeficiency and undetectable infectious virions in LSEC or KC [25]. However, viral replication in liver was similar for pathogenic parental virus and attenuated variants [26], suggesting that the gravity of hepatitis depends on the intensity of the inflammatory response. Finally, a non-pathogenic YAC-MHV3 variant, isolated from a persistent viral infection in YAC-1 cells, induces subclinical hepatitis characterized by few perivascular local inflammatory foci, and subsequent recovery occurring within less than 15 days [27].…”