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

Year: 2025

Type: article

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. Previous studies have identified NAD+ metabolism imbalances in the brains of ZIKV-infected mice, but the molecular basis underlying this disruption remains unclear. Here, we investigated these mechanisms using a neonatal ZIKV-infection mouse model, which developmentally corresponds to third-trimester infection in humans. Postnatal day 3 (P3) mice were subcutaneously infected with ZIKV or Mock-infected, and groups were euthanized every three days until 30 dpi to assess changes in brain metabolism and inflammation. 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. However, at later stages, NAD+ depletion strongly aligned with the upregulation of CD38 expression and activity. CD38 inhibition with Ab68 prevented NAD+ depletion, reinforcing its role as a major NADase in this context. Additionally, 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. Thus, our findings indicate that CD38 plays a central role in NAD+ depletion in the brains of ZIKV-infected mice, likely driven by neuroinflammation and immune cell infiltration. These insights highlight a potential therapeutic target for preserving NAD+ homeostasis in ZIKV-associated neurological complications.

Source: iScience

DOI: 10.1016/j.isci.2025.114018