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Matrix metalloproteinase expression correlates with virulence following neurotropic mouse hepatitis virus infection
Jiehao Zhou1, Stephen A Stohlman, Roscoe Atkinson
1Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
Abstract:
The relationship(s) between viral virulence and matrix metalloproteinase (MMP) expression in the central nervous system (CNS) of mice undergoing lethal and sublethal infections with neurotropic mouse hepatitis virus was investigated. Lethal infection induced increased levels of MMP-3 and MMP-12 mRNAs as well as that of tissue inhibitor of matrix metalloproteinases 1 (TIMP-1) compared to sublethal infection. Increased induction of MMP, TIMP, and chemokine expression correlated with increased virus replication but not with inflammatory cell infiltration. Infection of immunosuppressed mice suggested that expression of most MMP, TIMP, and chemokine mRNA was induced primarily in CNS-resident cells. By contrast, MMP-9 protein activity was associated with the infiltration of neutrophils into the CNS. These data indicate an association between the magnitude of inflammatory gene expression within the CNS and viral virulence.
Insights
Viral virulence correlates with inflammatory gene expression in the central nervous system (CNS). Lethal mouse hepatitis virus infections increased matrix metalloproteinase (MMP) and tissue inhibitor of matrix metalloproteinases (TIMP) mRNA levels, primarily in CNS-resident cells.
Area of Science:
- Neurovirology
- Immunology
- Molecular Biology
Background:
- Viral infections of the central nervous system (CNS) can lead to significant morbidity and mortality.
- Matrix metalloproteinases (MMPs) are enzymes involved in tissue remodeling and inflammation, and their role in neuroinflammation is increasingly recognized.
- Understanding the interplay between viral virulence and host inflammatory responses in the CNS is crucial for developing therapeutic strategies.
Purpose of the Study:
- To investigate the relationship between viral virulence and the expression of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in the CNS.
- To determine whether MMP and chemokine expression is linked to viral replication or inflammatory cell infiltration.
- To identify the cell types responsible for MMP and chemokine induction in the CNS during viral infection.
Main Methods:
- Mice were infected with neurotropic mouse hepatitis virus (MHV) to establish lethal and sublethal infection models.
- Quantitative real-time PCR was used to measure mRNA levels of MMPs, TIMPs, and chemokines in CNS tissues.
- MMP-9 enzymatic activity was assessed using zymography.
- Experiments involving immunosuppressed mice were conducted to differentiate between CNS-resident and infiltrating cell contributions.
Main Results:
- Lethal MHV infection resulted in significantly higher levels of MMP-3, MMP-12, and TIMP-1 mRNA compared to sublethal infections.
- Increased expression of MMPs, TIMPs, and chemokines correlated positively with viral replication but not with the extent of inflammatory cell infiltration.
- Infection of immunosuppressed mice indicated that most MMP, TIMP, and chemokine mRNA induction originated from CNS-resident cells.
- MMP-9 protein activity was specifically associated with neutrophil infiltration into the CNS.
Conclusions:
- The magnitude of inflammatory gene expression within the CNS is associated with the virulence of the infecting virus.
- While CNS-resident cells are the primary source of MMP, TIMP, and chemokine mRNA induction, neutrophil infiltration contributes to MMP-9 activity during severe infections.
- These findings highlight a complex interplay between viral load, host cell responses, and specific MMP activities in the pathogenesis of neurotropic viral infections.