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The art of survival during viral persistence
Stephen A Stohlman1, Chandran Ramakrishna, Shuen-Ing Tschen
1Department of Neurology, University of Southern California Keck School of Medicine, Los Angeles, California 90033, USA. stohlman@usc.edu
Abstract:
Central nervous system infection by the neurotropic JHM strain of mouse hepatitis virus (JHMV) results in chronic demyelination characterized by viral persistence in the absence of infectious virus. CD8(+) T cells inhibit acute viral replication via cell type-specific effector mechanisms. Perforin-mediated cytolysis controls virus in microglia/macrophages and astrocytes, whereas interferon (IFN)-gamma regulates viral replication in oligodendroglia. JHMV infection of antibody-deficient mice confirmed a primary role of cellular immunity and a redundant role for humoral immunity during acute infection. However, infectious virus reactivates in antibody-deficient mice following viral clearance. This observation suggests that virus-specific T cells in the central nervous system are unable to control viral persistence. Reactivation in antibody-deficient mice is not associated with increased T-cell infiltration, but is prevented via transfer of neutralizing antibody. A vital role for humoral immunity during persistence is supported by the accumulation and retention of virus-specific antibody secreting cells following clearance of infectious virus. Thus, cell-mediated immune responses control acute infection, whereas humoral immunity maintains viral persistence. Therefore, although the central nervous system provides an environment for prolonged retention of both T cells and plasma cells, plasma cells are critical in maintaining persistent virus at undetectable levels. The low turnover of virus, T cells, and B cells constitute a unifying feature of persistent infection, illustrating the dichotomy between distinct immune effectors in regulating acute and persistent central nervous system infection.
Insights
Cell-mediated immunity controls acute mouse hepatitis virus (JHMV) infection, while humoral immunity is crucial for maintaining viral persistence in the central nervous system. Antibody-producing plasma cells are vital for keeping the virus undetectable long-term.
Area of Science:
- Neuroimmunology
- Virology
- Immunology
Background:
- Mouse hepatitis virus (JHMV) causes chronic demyelination in the central nervous system (CNS) with persistent virus.
- CD8(+) T cells employ distinct mechanisms to control acute JHMV replication in different CNS cell types.
Purpose of the Study:
- To investigate the distinct roles of cell-mediated and humoral immunity in controlling acute and persistent JHMV infection within the CNS.
Main Methods:
- JHMV infection in wild-type and antibody-deficient mice.
- Analysis of viral replication, T cell responses, and antibody-secreting cells.
- Assessment of viral reactivation and control through antibody transfer.
Main Results:
- Cell-mediated immunity (perforin, IFN-gamma) controls acute JHMV replication.
- Humoral immunity is essential for preventing viral reactivation and maintaining persistence.
- Virus-specific antibody-secreting cells accumulate in the CNS and are critical for long-term viral control.
Conclusions:
- Cell-mediated immunity is sufficient for acute JHMV control, but humoral immunity is indispensable for long-term viral persistence.
- Plasma cells in the CNS play a critical role in maintaining persistent JHMV at undetectable levels.
- Distinct immune effector mechanisms regulate acute versus persistent CNS viral infections.