Abstract
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 Parp10 or Parp12 induction, which increased alongside Nampt 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 (Il-6, Tnf, and Ccl5/Rantes) and coincided with the infiltration of CD38+ immune cells - especially lymphocytes - into the brain, suggesting a link between neuroinflammation and NAD+ metabolism dysregulation.