Programmed cell death of infected cells is an ancient pathway of host defense. We now understand that cells can undergo distinct forms of programmed cell death: in addition to apoptosis, necroptosis is a recently-described form of cell suicide that can be induced by viral infection. Necroptosis involves cellular swelling and rupture, and has been hypothesized to trigger inflammatory and immune responses when it occurs in vivo, making the necroptotic pathway a form of host-inducible tissue damage. While this may be an effective strategy in tissues with high regenerative potential and the ability to sustain high inflammatory burdens, it is likely to be detrimental in essential tissues lacking these features, such as the CNS. To test these ideas, we assessed the role of the necroptotic pathway in defense against the neurotropic flavivirus West Nile virus (WNV), and found that while the key necroptotic kinase RIPK3 is required for CNS-intrinsic defense against WNV, necroptotic cell death does not play a role in this pathway. Rather, RIPK3 coordinates a transcriptional response essential for chemokine production and recruitment of inflammatory leukocytes to the brain. Based on these preliminary data, we hypothesized that the CNS represents a tissue that is ?cell death privileged,? in which inflammatory forms of cell death do not represent a beneficial form of host defense. Further, we propose that in these tissue, the pathway of necroptosis has taken on non-death roles in coordinating innate immune defense. To assess this idea, we will take complimentary approaches, first by deleting and then by forcing activation of necroptotic pathway components in the brain. Aim 1: We will use a conditional RIPK3flox allele to delete this essential necroptotic kinase within specific cell types in the CNS, then assess both cell death and transcriptional responses to both innate immune stimulation and WNV infection. Aim 2: We will make use of a new animal model, developed in our lab, in which RIPK3 can be specifically activated using a ligand drug. We will activate RIPK3 in specific neuronal tissues, then measure resulting transcriptional responses, chemokine production, neuroinflammation and neuropathology. Together, the experiments described here will expand our understanding of the link between cell death and inflammation, and will also identify a novel axis of innate immune response to a neurotropic virus representing a human health threat.