| Though neurons can be productively infected with measles virus (MV), they do not display two of the cardinal hallmarks of peripheral infection: release of extracellular virions and associated cytopathicity due to syncytia formation. How neurons survive MV infection, as well as other neurotropic viral infections, may be due to induction of a unique profile of interferon-inducible genes. One of these genes, BST-2, inhibits release of enveloped viruses. Based on this observation, we investigated the ability of interferons and MV infection to induce BST-2 in primary neurons, and to explore the consequences of BST-2 expression on MV release. Despite low basal BST-2 expression in neurons as compared to primary fibroblasts and glial cells, Type I (IFNbeta) and Type II interferon (IFNgamma) exposure significantly induced BST-2 expression in neurons. MV-infection of neurons also elevated BST-2 levels, though interestingly, another enveloped RNA virus, lymphocytic choriomeningitis virus (LCMV), did not affect BST-2 levels, perhaps because of its capacity to block the host interferon response. This finding led us to investigate how MV induces BST-2. Utilizing neurons from Type I interferon receptor knockout (IFNAR KO) mice and STAT1 knockout mice, we found that MV upregulation of BST-2 is dependent on IFN production and signaling via STAT1, not viral replication itself. A cell line expressing tetracycline-inducible BST-2 was employed to show that extracellular MV is, in fact, limited by BST-2 expression.;Historically, interferons are known to inhibit viral spread and contain infection. Moreover, IFNgamma is recognized as a critical mediator of neurotropic MV infection. Although IFNgamma is crucial for non-cytolytic clearance of MV in vivo, the mechanisms by which it protects neurons from death and viral release are unknown. Type I interferons and IFNy were examined for their ability to limit viral RNA production and spread. Of note, Type I interferons and IFNgamma inhibited MV via different mechanisms: Type I interferons restricted extracellular MV release, while IFNgamma limited neuron-to-neuron spread. These findings will enable us to better understand the cell-specific responses to interferons induced by viral infection, and will elucidate how interferons function in the unique environment of the CNS. |
