CD38 is a key mediator of NAD+ depletion in the brain of ZIKV-infected mice

Zika virus (ZIKV) infection is a major health concern, particularly during pregnancy, as it can lead to neurodevelopmental delays and congenital brain abnormalities, including microcephaly. Here, we investigated the mechanisms of NAD⁺ depletion in the brains of ZIKV-infected neonatal mice, a model that developmentally corresponds to third-trimester infection in humans. We observed a progressive decline in NAD⁺ levels, which became significant at later stages of infection (18-30 dpi). This decrease did not correlate with viral replication and early <i>Parp10</i> or <i>Parp12</i> induction, which increased alongside <i>Nampt</i> expression, possibly as a compensatory response to NAD⁺ consumption. Instead, NAD⁺ depletion coincided with increased CD38 expression and activity, while CD38 inhibition prevented NAD⁺ loss. Late-stage NAD⁺ depletion was preceded by an induction of inflammatory markers (<i>Il-6</i>, <i>Tnf</i>, and <i>Ccl5/Rantes</i>) and coincided with the infiltration of CD38⁺ immune cells - especially lymphocytes - into the brain, suggesting a link between neuroinflammation and NAD⁺ metabolism dysregulation.