Neurons are essential and nonrenewable cells; consequently, irreversible CNS disease could result from either replication of a cytotoxic virus, or from cytotoxic T lymphocyte (CTL)-mediated lysis of infected neurons. To protect against these outcomes, immune strategies must exist to eliminate CNS pathogens with a minimum of neuronal death. We have obtained evidence to suggest that measles virus-infected neurons produce chemokines that specifically recruit T lymphocytes into the CNS, implicating a crucial role for neurons in the initiation of the anti-viral immune response. Moreover, clearance of measles virus is associated with massive T cell infiltration, which eliminates the virus without concomitant neuronal death. Importantly, while these processes occur in adult mice, neonates succumb to CNS infection, despite mounting a robust immune response. In the proposed studies, a combination of neuronal cell culture systems and a novel transgenic mouse model will be used to characterize the basis for noncytopathic clearance of measles virus from infected neurons. Because infection of these mice is governed by the transgenic expression of the human receptor, virus infection is restricted to CNS neurons. This model will be used to address two fundamental, yet unresolved questions: 1) How do chemokines, synthesized within the immune-privileged environment of the CNS, result in recruitment of the antiviral response?, and 2) What is the mechanism of noncytolytic inhibition of virus replication in neurons? The long-term goals of our research are to understand how noncytolytic antiviral defenses are regulated, and to compare these findings to cases in which these defenses fail. Ultimately, the results of these studies will be used to determine how the immune response may have evolved to eliminate damaging pathogens while preserving a critical cell population. Understanding the mechanism by which this occurs will inform the development of immune-based strategies to resolve viral infections associated with human mental illness and disease.
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