Persistent measles virus in the brain after resolution of acute infection

University Of Pennsylvania, Philadelphia PA

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Abstract

? DESCRIPTION (provided by applicant): Viral infections of the central nervous system (CNS) can lead to debilitating diseases such as encephalitis, resulting in long lasting neurological defects, and often cause death. Viral persistence and latency within the CNS is generally not considered for potentially neurotropic RNA viruses such as measles virus (MV), which is thought to be sterilely cleared after acute infection. However, RNA viruses can cause CNS disease presenting months to years after the initial infection, raising the possibility of viral recurrence long after resolution of the acute infection. Furthermore, it has been shown that MV RNA persists in the CNS of elderly individuals who died of natural causes, implicating retention of replication-competent virus decades after primary exposure. Our laboratory has shown that immunocompetent C57Bl/6 mice, engineered to express a measles virus receptor in CNS neurons, can functionally resolve MV from the CNS with no lasting neurological defects. However, viral RNA and mRNA persist in the brains of these mice for greater than 90 days after viral challenge. After depletion of the adaptive immune response in these persistently infected mice, the levels of MV RNA, mRNA, and protein increased within the CNS, suggesting a role for the immune response in restricting active viral replication. It is becoming increasingly clear that the adaptive immune system tailors its effector function toward specific pathogens based on the tissue and cell type that is infected (i.e., by promoting non-cytolytic clearance of nonrenewable cell populations such as neurons). The goal of this proposal is to identify the specific effector cells of the adaptive immune system responsible for suppressing MV replication long after an acute infection. Moreover, I will identify and define CNS regions and cell types that are harboring persistent MV capable of reactivation, further illuminating fundamental differences between neuronal cell types. A better understanding of how RNA viruses persist within the CNS and the mechanisms that lead to viral reactivation will provide a much needed understanding of the host response to viral infection in nonrenewable cell populations. Completion of these experiments will illuminate how viruses--once believed to be sterilely cleared--may lead to CNS disease long after acute infection. This work is of direct relevance to human CNS diseases with an inflammatory component, but of unknown or poorly defined etiology, including Alzheimer's, multiple sclerosis, and amyotrophic lateral sclerosis.