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Mouse hepatitis virus neurovirulence: evidence of a linkage between S glycoprotein expression and immunopathology
Julia D Rempel1, Shannon J Murray, Jeffrey Meisner
1Division of Virology, Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Abstract:
Differences in disease outcome between the highly neurovirulent MHV-JHM and mildly neurovirulent MHV-A59 have been attributed to variations within the spike (S) glycoprotein. Previously, we found that MHV-JHM neurovirulence was marked by diminished expression of interferon-gamma (IFN-gamma) mRNA and a reduced presence of CD8 T cells in the CNS concomitant with heightened macrophage inflammatory protein (MIP)-1 transcript levels and greater macrophage infiltration relative to MHV-A59 infection. Here, the ability of the S and non-spike genes to regulate these immune responses was evaluated using chimeric viruses. Chimeric viruses WTR13 and S4R22 were made on MHV-A59 variant backgrounds and, respectively, contained the S gene of MHV-A59 and MHV-JHM. Unexpectedly, genes other than S appeared to modulate events critical to viral replication and survival. Unlike unresolving MHV-JHM infections, the clearance of WTR13 and S4R22 infections coincided with strong IFN-gamma transcription and an increase in the number of CD8 T cells infiltrating into the CNS. However, despite the absence of detectable viral titers, approximately 40% of S4R22-infected mice succumbed within 3 weeks, indicating that the enhanced mortality following S4R22 infection was not associated with high viral titers. Instead, similar to the MHV-JHM infection, reduced survival following S4R22 infection was observed in the presence of elevated MIP-1alpha and MIP-1beta mRNA accumulation and enhanced macrophage numbers within infected brains. These observations suggest that the S protein of MHV-JHM influences neurovirulence through the induction of MIP-1alpha- and MIP-1beta-driven macrophage immunopathology.
Insights
Non-spike genes in mouse hepatitis virus (MHV) influence neurovirulence by modulating immune responses. The spike (S) protein specifically drives macrophage immunopathology via MIP-1alpha and MIP-1beta, impacting disease outcome.
Area of Science:
- Virology
- Immunology
- Neuroscience
Background:
- Murine hepatitis virus (MHV) strains MHV-JHM and MHV-A59 exhibit distinct neurovirulence.
- Previous studies linked MHV-JHM neurovirulence to specific immune responses, including interferon-gamma (IFN-gamma) mRNA expression, CD8 T cell infiltration, and macrophage inflammatory protein (MIP)-1 levels in the central nervous system (CNS).
Purpose of the Study:
- To investigate the roles of the spike (S) glycoprotein and other viral genes in modulating MHV-induced immune responses and neurovirulence.
- To determine whether non-S genes contribute to the differential disease outcomes observed between MHV-JHM and MHV-A59 infections.
Main Methods:
- Construction of chimeric MHV viruses (WTR13 and S4R22) using MHV-A59 backgrounds with either the MHV-A59 or MHV-JHM S gene.
- Infection of mice with chimeric viruses and analysis of viral replication, immune cell infiltration (CD8 T cells, macrophages), and gene expression (IFN-gamma, MIP-1alpha, MIP-1beta) in the CNS.
Main Results:
- Chimeric viruses demonstrated that genes other than S significantly influenced viral replication and survival.
- Clearance of WTR13 and S4R22 infections correlated with robust IFN-gamma transcription and increased CD8 T cell infiltration.
- Despite low viral titers, S4R22 infection led to increased mortality, associated with elevated MIP-1alpha and MIP-1beta mRNA and heightened macrophage infiltration in the brain, similar to MHV-JHM infection.
Conclusions:
- The S protein of MHV-JHM contributes to neurovirulence by inducing MIP-1alpha and MIP-1beta, which drive macrophage-mediated immunopathology.
- Non-S genes play a critical role in regulating viral replication and immune responses, impacting the overall disease outcome independently of the S protein's direct effects.
