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A dual-pronged host-directed therapeutic targeting cyclophilin A and pathogenic interferon response abrogates

Wenzhe Yu1,2, Hongmin Cao2, Zhifang Deng2

  • 1Department of Obstetrics and Gynecology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.

Nature Communications
|May 29, 2026
PubMed

Insights

Cyclophilin A (CypA) is essential for Zika virus (ZIKV) replication in the placenta. Inhibiting CypA with ciclosporin A (CsA) blocks ZIKV transmission and reduces fetal harm.

Area of Science:

  • Virology and Immunology
  • Maternal-Fetal Medicine
  • Drug Discovery

Background:

  • Pathogenic viruses can transmit vertically, causing placental immunopathology and threatening fetal development.
  • Mechanisms of viral pathogenesis and effective therapeutics for congenital infections remain significant research gaps.

Purpose of the Study:

  • To identify host factors crucial for Zika virus (ZIKV) replication in human placental cells.
  • To investigate the therapeutic potential of targeting these host factors against ZIKV and related pregnancy complications.

Main Methods:

  • Investigated the role of cyclophilin A (CypA) in ZIKV replication within human placental trophoblasts.
  • Utilized genetic ablation of CypA and pharmacological inhibition with ciclosporin A (CsA).
  • Assessed ZIKV transplacental transmission, placental pathology, and fetal outcomes.
  • Analyzed the impact of CsA on type I interferon signaling pathways (JAK1-STAT1/2).

Main Results:

  • Cyclophilin A (CypA) is essential for ZIKV replication in placental trophoblasts, independent of its known functions.
  • ZIKV infection recruits CypA, disrupting host RNA decay and antiviral surveillance.
  • Genetic deletion or CsA inhibition of CypA significantly restricted ZIKV transplacental transmission and associated pathologies.
  • CsA also ameliorated type I interferonopathies by inhibiting the JAK1-STAT1/2 pathway.

Conclusions:

  • Cyclophilin A (CypA) is a critical host factor in ZIKV pathogenesis and placental infection.
  • Ciclosporin A (CsA) demonstrates dual efficacy by inhibiting ZIKV replication and counteracting pathological interferon responses.
  • CsA represents a promising therapeutic candidate for managing congenital viral infections and pregnancy-specific interferonopathies.

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