Alzate, D. | bioRxiv Science

bioRxiv2026

SIRT1 remodels astrocyte metabolism and promotes viral replication during neurotropic orthoflavivirus infection

Orthoflaviviruses depend on host metabolic resources to replicate, but how distinct cell types in the central nervous system (CNS) alter their metabolism in response to infection remains incompletely understood. Here, we examined whether the NAD+-dependent deacetylase SIRT1 is engaged during Zika virus (ZIKV) and West Nile virus (WNV) infection and whether its activity influences infection outcomes. SIRT1 activity increased in astrocytes isolated from infected mouse brains and in infected primary human astrocytes, but not in neurons or CNS myeloid cells. In astrocytes, infection induced transcriptomic, metabolomic, and functional changes consistent with SIRT1 activation, enhanced NAD+ salvage, and enhanced oxidative metabolism. Pharmacologic inhibition of SIRT1 or NAD+ salvage reduced ZIKV replication in astrocytes, whereas SIRT1 activation or supplementation with an NAD+ precursor increased replication. In mice, SIRT1 inhibition or nicotinamide (NAM) treatment reduced viral burden and mortality following ZIKV and WNV infection, while SIRT1 activation worsened disease. Together, these findings identify NAD+/SIRT1 as key regulators of cellular metabolism in infected astrocytes and support a role for this pathway in promoting orthoflavivirus replication and pathogenesis.

immunology↗

bioRxiv2023

Neuronal DAMPs exacerbate neurodegeneration via astrocytic RIPK3 signaling

Astrocyte activation is a common feature of neurodegenerative diseases. However, the ways in which dying neurons influence the activity of astrocytes is poorly understood. RIPK3 signaling has recently been described as a key regulator of neuroinflammation, but whether this kinase mediates astrocytic responsiveness to neuronal death has not yet been studied. Here, we used the MPTP model of Parkinsons disease to show that activation of astrocytic RIPK3 drives dopaminergic cell death and axon damage. Transcriptomic profiling revealed that astrocytic RIPK3 promoted gene expression associated with neuroinflammation and movement disorders, and this coincided with significant engagement of DAMP signaling. Using human cell culture systems, we show that factors released from dying neurons signal through RAGE to induce RIPK3-dependent astrocyte activation. These findings highlight a mechanism of neuron-glia crosstalk in which neuronal death perpetuates further neurodegeneration by engaging inflammatory astrocyte activation via RIPK3.

neuroscience↗