Many different viruses exploit the odorant system to enter the central nervous system. Using a prototypic neurotropic virus, vesicular stomatitis virus (VSV), we found that upon intranasal instillation the virus infects olfactory sensory neurons in the nasal epithelium and then moves along the axons into the glomerular layer of the olfactory bulb. There, virus spread is inhibited in a type I interferon dependent manner. Our more recent studies indicated that upon intranasal VSV infection astrocytes within the olfactory bulb show abundant interferon-beta expression that exhibits long-distance effects even in more distal parts of the brain. Six days after infection massive microglia accumulation and activation is detected in peripheral areas of the olfactory bulb, thus forming an innate immune shield covering the entire olfactory bulb. Depletion of microglia during the infection resulted in enhanced virus spread and lethality. Surprisingly, VSV induced microglia activation, proliferation, and accumulation of myeloid cells was regulated by type I IFN receptor (IFNAR) signaling of astrocytes and neurons, but not of microglia. Animals lacking IFNAR signaling in astrocytes and neurons died after intranasal VSV infection, whereas animals lacking IFNAR signaling on microglia survived. Thus, in the infected CNS crosstalk between astrocytes, neurons, and microglia is critical for full microglia activation and protection during viral encephalitis.