- Metabolic regulation of viral encephalitis As long-lived cells with limited capacity for self-renewal, neurons employ unique strategies to resist pathogen infection while limiting immunopathology. We recently described one such pathway, using models of Zika (ZIKV)and West Nile virus (WNV)-induced encephalitis: We found that these infections lead to up- regulation of the metabolic enzyme IRG1 and accumulation of its product, the metabolite itaconate, within infected neurons. Itaconate potently inhibits succinate dehydrogenase, a key component of energetic metabolism. The resultant alteration in neuronal metabolism limits viral replication within neurons, and was required for survival to these models of viral encephalitis. Notably, the IRG1/itaconate metabolic axis has received significant recent attention for its role in limiting inflammatory responses in peripheral macrophages. As viral encephalitis is also characterized by neuroinflammation, and as IRG1 is upregulated along with a host cytokines and chemokines within the CNS, we hypothesize that IRG1-mediated itaconate production alters neuronal metabolism to limit both viral replication and neuroinflammation. Interestingly, our data indicate that itaconate is both secreted and taken up by cultured cells, leading us to further hypothesize that itaconate is a diffusible molecule capable of broadly altering viral susceptibility and metabolism across tissue microenvironments. To test these hypotheses, we will first investigate the mechanism by which itaconate-mediated metabolic alterations restrict viral replication in neurons. We will then investigate the anti-inflammatory role of itaconate, assessing both its cell-intrinsic function and its putative role as a diffusible ?metabokine.?
/Relevance statement Neurons use unique strategies to combat viral infection. This application will investigate a newly-discovered mechanism by which neurons alter their metabolism in response to infection to limit viral replication and prevent damage to the central nervous system.
