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<p>Pathogenic viruses threaten fetal development by achieving vertical transmission and instigating placental immunopathology, while the pathobiological mechanisms and effective therapeutics remain critical gaps. Here, we reveal cyclophilin A (CypA) as a crucial host factor necessary for Zika virus (ZIKV) replication in human placental trophoblasts, acting independently of its canonical functions. ZIKV infection recruits CypA into the viral replication organelle and reconfigures its interactome, thereby subverting host RNA decay machinery and stress granule-mediated antiviral surveillance. Both genetic ablation of CypA and its pharmacological inhibition with clinically approved drug ciclosporin A (CsA) restrict ZIKV transplacental transmission and corresponding placental and fetal pathologies. Beyond its anti-ZIKV potency, CsA concurrently counteracts pathological type I interferon signaling by targeting the JAK1-STAT1/2 pathway, broadly ameliorating pregnancy-specific interferonopathies driven by viral infection or endogenous double-stranded RNA stress. Our findings elucidate CypA-governed ZIKV pathogenesis and license CsA as a promising dual-action therapeutic to counteract congenital viral infections.</p>

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A dual-pronged host-directed therapeutic targeting cyclophilin A and pathogenic interferon response abrogates virus-triggered pregnancy pathologies

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月29日

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  • Wenzhe Yu,
  • Hongmin Cao,
  • Zhifang Deng,
  • Jiahao Chen,
  • Beiang Zhang,
  • Shuai Zhu,
  • Dunjin Chen,
  • Xiaoqian Hu,
  • Bin Cao

摘要

Pathogenic viruses threaten fetal development by achieving vertical transmission and instigating placental immunopathology, while the pathobiological mechanisms and effective therapeutics remain critical gaps. Here, we reveal cyclophilin A (CypA) as a crucial host factor necessary for Zika virus (ZIKV) replication in human placental trophoblasts, acting independently of its canonical functions. ZIKV infection recruits CypA into the viral replication organelle and reconfigures its interactome, thereby subverting host RNA decay machinery and stress granule-mediated antiviral surveillance. Both genetic ablation of CypA and its pharmacological inhibition with clinically approved drug ciclosporin A (CsA) restrict ZIKV transplacental transmission and corresponding placental and fetal pathologies. Beyond its anti-ZIKV potency, CsA concurrently counteracts pathological type I interferon signaling by targeting the JAK1-STAT1/2 pathway, broadly ameliorating pregnancy-specific interferonopathies driven by viral infection or endogenous double-stranded RNA stress. Our findings elucidate CypA-governed ZIKV pathogenesis and license CsA as a promising dual-action therapeutic to counteract congenital viral infections.