Demyelinating encephalitis is a type of encephalitis in which the insulating myelin sheath surrounding nerve fibers is damaged. Most types of demyelinating encephalitis are known to be caused by viral infection, and therefore the nature of viral persistence in the central nervous system (CNS) has become crucial to understanding the pathogenesis of associated diseases. Subacute sclerosing panencephalitis (SSPE) is a progressive fatal demyelinating disease caused by infection with high levels of neuronal measles virus (MV) in the CNS. Thus, MV infection provides one of the main paradigms of persistent viral infection that causes encephalitis. Many reviews have been published explaining how MV establishes a persistent infection in the CNS [1, 2, 3]. A number of studies on SSPE using cDNA cloning and sequencing techniques have revealed that MV genomes are present in samples obtained from SSPE patients. This demonstrates the presence of mutations that may lead to MV persistence in the CNS. However, no study has been able to explain how persistent MV is reactivated and results in subsequent pathogenesis of the CNS. In this review, we describe a brief overview of MV and SSPE. We will attempt to focus on host cell modifications related to MV persistence, and on reactivation mechanisms of MV during persistent infections. We will then discuss the pathogenesis of persistent MV infections in patients to highlight molecular events that lead to the manifestation of SSPE symptoms. These key advances in the understanding of MV persistence will provide novel insights into the elucidation of SSPE pathogenesis.
2. Measles and the CNS sequelae
3. Host cell modifications in MV persistence
4. Reactivation mechanisms of persistent MV
It is known that persistent MV infection is asymptomatic but can eventually result in SSPE . The latent MV should be reactivated at the onset of disease, resulting in clinical signs of SSPE (Figure 1C). However, the molecular mechanisms of MV persistence and reactivation are yet to be elucidated.
5. Pathogenesis of persistent MV infection
MV infection induces clinically significant immunosuppression, which can continue for many weeks after an apparent recovery from measles [50, 51]. Long-lived cytokine imbalances and direct effects on the proliferation of lymphocytes are reportedly implicated with the immunosuppression. In contrast, a persistent brain infection leads to a hyperimmune antibody response, a pathogenic feature of SSPE [10, 11]. For example, there are extremely high titers of neutralizing antibodies in the serum and CSF against viral structural proteins. The immune system would appear to be involved in SSPE pathogenesis (Figure 1D).
Many previous studies have demonstrated that changes in host cell homeostasis contribute to the pathogenesis of persistent MV infections. Rapid replication of MV that has been quiescent for years is triggered by some reactivation event(s) and results in hyper-reactive immune responses. Demyelination in persistent MV infections is due to a complex combination of viral cytopathic effects on neuronal cells and immune-mediated mechanisms. Although the pathogenesis of persistent MV infection remains to be fully elucidated, some of the key advances outlined in this review will provide novel insights into the understanding of human demyelinating encephalitis, and other encephalitis types induced by viruses.
AcknowledgmentsThis work was supported by Grants-in-Aid for Scientific Research (KAKENHI) from the Japan Society for the Promotion of Science (JSPS), and in part by Global COE Program “Center of Education and Research for the Advanced Genome-Based Medicine: For personalized medicine and the control of worldwide infectious diseases”, Ministry of Education, Culture, Sports, Science and Technology, Japan.
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