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<p>Zika virus (ZIKV) infection of the developing brain induces neuroinflammatory responses that can restrict viral replication but may also contribute to neurological injury when dysregulated. Although neuronal phospholipid homeostasis is critical for membrane integrity and synaptic function, how ZIKV infection reprograms lipid metabolism to drive neuropathogenesis remains unclear. Here, we identify calcium-independent phospholipase A2β (iPLA2β) as a key mediator of ZIKV-induced neuronal lipid remodeling. iPLA2β is rapidly upregulated in neurons and in the neonatal brain following infection, and its expression is promoted by the viral envelope protein, which interacts with iPLA2β in neurons. Genetic ablation of iPLA2β reduces viral burden in the developing brain and in primary neurons and disrupts ZIKV-induced phospholipid remodeling, characterized by altered arachidonic acid–containing phospholipids and depletion of docosahexaenoic acid-enriched species. Importantly, sustained iPLA2β activity promotes phospholipid remodeling that supports efficient ZIKV replication, thereby increasing viral burden and contributing to a pro-inflammatory lipid environment. This is associated with increased prostaglandin E₂ production, glial activation, and neuronal loss. Both genetic and pharmacological inhibition of iPLA2β partially restores phospholipid homeostasis and reduces viral burden, accompanied by attenuation of neuroinflammatory responses. Functionally, targeting iPLA2β improves survival and neurobehavioral outcomes and mitigates long-term cognitive deficits following neonatal ZIKV infection. Collectively, these findings support iPLA2β-dependent phospholipid remodeling as a host process that facilitates ZIKV replication and links infection to neuroinflammation and neurological injury, highlighting iPLA2β as a potential therapeutic target in ZIKV-associated neuropathogenesis.</p>

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iPLA2β-dependent phospholipid remodeling drives ZIKV-induced neuroinflammation and neurological injury

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月20日

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  • Li Jiao,
  • Wenxin Shao,
  • Ying Xie,
  • Sirong Li,
  • Jiahong Gao,
  • Jianyu Xu,
  • Rui Tong,
  • Dehong Li,
  • Qiangming Sun

摘要

Zika virus (ZIKV) infection of the developing brain induces neuroinflammatory responses that can restrict viral replication but may also contribute to neurological injury when dysregulated. Although neuronal phospholipid homeostasis is critical for membrane integrity and synaptic function, how ZIKV infection reprograms lipid metabolism to drive neuropathogenesis remains unclear. Here, we identify calcium-independent phospholipase A2β (iPLA2β) as a key mediator of ZIKV-induced neuronal lipid remodeling. iPLA2β is rapidly upregulated in neurons and in the neonatal brain following infection, and its expression is promoted by the viral envelope protein, which interacts with iPLA2β in neurons. Genetic ablation of iPLA2β reduces viral burden in the developing brain and in primary neurons and disrupts ZIKV-induced phospholipid remodeling, characterized by altered arachidonic acid–containing phospholipids and depletion of docosahexaenoic acid-enriched species. Importantly, sustained iPLA2β activity promotes phospholipid remodeling that supports efficient ZIKV replication, thereby increasing viral burden and contributing to a pro-inflammatory lipid environment. This is associated with increased prostaglandin E₂ production, glial activation, and neuronal loss. Both genetic and pharmacological inhibition of iPLA2β partially restores phospholipid homeostasis and reduces viral burden, accompanied by attenuation of neuroinflammatory responses. Functionally, targeting iPLA2β improves survival and neurobehavioral outcomes and mitigates long-term cognitive deficits following neonatal ZIKV infection. Collectively, these findings support iPLA2β-dependent phospholipid remodeling as a host process that facilitates ZIKV replication and links infection to neuroinflammation and neurological injury, highlighting iPLA2β as a potential therapeutic target in ZIKV-associated neuropathogenesis.