Neural stem/progenitor cell fate: pathology and protection during CNS infections

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DESCRIPTION (provided by applicant): Many diverse viruses cause devastating central nervous system (CNS) infections in the United States (e.g. herpesvirus, HIV, arboviruses), leading to severe encephalitis, long-term neurological sequelae (seizures, cognitive deficits, developmental disorders, etc.), and death. Though the immune system vigorously responds to the virus, CNS infections are associated with acute damage to neurons and loss of neural stem/progenitor cells (NSPCs). The immune response may even contribute to neuropathology through bystander effects on uninfected cells near the infection. For example, NSPCs are responsive to many pro-inflammatory mediators, which disrupt the production of new neurons by the NSPCs and potentially inhibit CNS repair. The interactions between the virus, the immune response, and NSPCs are not well understood, and therapeutic modalities for protecting NSPCs or modulating anti-viral immunity in the CNS are lacking. We have recently characterized the role of interferon-gamma (IFNγ), an anti-viral cytokine produced by immune cells, during CNS infections. We hypothesize that IFNγ drives NSPCs toward production of new glia instead of new neurons, which could have profound effects on CNS repair. Using a transgenic mouse model of neuron-restricted measles virus infection in the brain (CD46+ mice), we have found that IFNγ preserves the NSPC pool but is unable to protect newly-born neurons in infected neonatal mice. We also observed increased expression of astrocytic markers in IFNγ-treated NSPCs, suggesting that IFNγ drives NSPCs toward production of new glia as opposed to new neurons. Importantly, in the CD46+ model, the virus is restricted to mature neurons, allowing for the analysis of inflammation on NSPCs without the confounding effects of direct NSPC infection. In Aim 1, we determine the role of critical components of the anti-viral response in altering NSPC proliferation and differentiation in neonatal and adult mice. We have crossed the CD46+ mice to a variety of immune-knockout backgrounds to study specifically the role of IFNγ and the immune cells that produce the majority of IFNγ (T-cells) in NSPC dysfunction. Thus, these experiments are distinctly suited to determine the effects of the anti-viral immune response on NSPCs during an infection. In Aim 2, we define the role of pro-inflammatory signaling molecules in cell fate decisions during IFNγ treatment in vitro and during an in vivo infection. We have established in vitro culture conditions for primary wildtype and knockout NSPCs, which we will use with pharmacological inhibitors and siRNA knockdown to identify signaling molecules that are involved in IFNγ signaling and cell fate choices. These studies are innovative because the role of the anti-viral immune response in NSPC dysfunction will be defined independently from the direct effects of the virus. Moreover, these studies will identify pro-inflammatory signaling molecules that dictate cell fate choice in NSPCs, establish a model system for defining and ameliorating the long-term neurological deficits from CNS infections, and propose a new approach for studying the effects of neuroinflammation on CNS development and repair.