PI3Kγ Pathway Contributes to Neuroinflammation and Neuronal Death Induced by Zika Virus Infection

ABSTRACT Zika virus (ZIKV) is an emerging arbovirus belonging to the Flaviviridae family and Orthoflavivirus genus, with a pronounced tropism for the central nervous system (CNS), where it induces neuroinflammation and neuronal death. ZIKV is known to exploit host cellular mechanisms, including the activation of survival pathways such as the PI3K/AKT signalling cascade, to evade apoptosis and enhance its replication. However, the role of the PI3Kγ isoform in ZIKV‐induced neuroinflammation has not been previously explored, and this study aimed to investigate PI3Kγ in ZIKV pathogenesis. Primary neuronal cultures from PI3Kγ‐deficient mice (PI3Kγ kd/kd ) and human neuroblastoma SH‐SY5Y cells treated with the PI3Kγ inhibitor AS605240 were infected with ZIKV to assess the impact of PI3Kγ signalling on viral replication and neuronal survival. Additionally, interferon α/β receptor knockout (A129) mice were treated with AS605240 either before or after ZIKV infection to evaluate the pathway's role in neuroinflammation. In vitro, both genetic ablation and pharmacological inhibition of PI3Kγ suppressed ZIKV replication (~3% and ~17%, respectively) and prevented neuronal death (~16%). In vivo, mice treated with the PI3Kγ inhibitor exhibited enhanced protection against ZIKV infection, characterised by reduced viral load (~12%) and diminished brain and optic nerve damage. This neuroprotective effect correlated with reduced TNF production (about ~67%) by microglia. Furthermore, inhibition of PI3Kγ curtailed the recruitment and activation of CD8+ T cells and decreased the production of pro‐inflammatory mediators, including IFN‐γ and IL‐17, in the brains of ZIKV‐infected mice. These findings suggest that PI3Kγ activation facilitates ZIKV infection and exacerbates neuroinflammation. Pharmacological inhibition of the PI3Kγ pathway may offer therapeutic benefits by limiting viral replication and alleviating neuroinflammatory responses during ZIKV infection.