Zika virus disrupts steroidogenesis and impairs spermatogenesis by stalling the translation of CYP17A1 mRNA

Wei Yang, Hanyu Li, Shanshan Wang, Rui Huang, Yifei Zhang, Moujian Guo, Li Huang, Shihua Li, Ruirui Yang, Dingran Zhao, Yuxin Xiong, Yifei Liu, Mengjing Huang, Lixia Hui, Wei Xiao and Ying Wu ()
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Wei Yang: Wuhan University
Hanyu Li: Wuhan University
Shanshan Wang: Wuhan University
Rui Huang: Wuhan University
Yifei Zhang: Wuhan University
Moujian Guo: Wuhan University
Li Huang: Wuhan University
Shihua Li: Chinese Academy of Sciences
Ruirui Yang: Chinese Academy of Sciences
Dingran Zhao: Wuhan University
Yuxin Xiong: Wuhan University
Yifei Liu: Wuhan University
Mengjing Huang: Wuhan University
Lixia Hui: Wuhan University
Wei Xiao: Wuhan University
Ying Wu: Wuhan University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract ZIKV infection is associated with testicular damage and abnormal spermatogenesis. However, the molecular mechanisms underlying these pathogenic processes remain unclear. Here, we demonstrate that ZIKV disrupts Leydig cells’ ability to produce testosterone, leading to decreased sperm counts and motility. Specifically, the non-structural protein NS2A of ZIKV downregulates testosterone production by directly binding to mRNA of CYP17A1, a key enzyme in testosterone synthesis, thereby inhibiting its translation. Notably, the sole membrane-traversing segment and its flanking loops of NS2A are crucial for this interaction with CYP17A1 mRNA. Scanning mutagenesis studies within this sequence identified amino acid residues critical for NS2A binding and the suppression of CYP17A1 mRNA translation. Testicular inoculation of adeno-associated virus (AAV) delivering ZIKV-NS2A or its mutant showed that ZIKV-NS2A alone is sufficient to affect steroidogenesis and spermatogenesis in vivo. Moreover, a mutant virus generated by reverse genetics, containing a single amino acid mutation that abolishes NS2A’s binding to CYP17A1 mRNA, exhibited significantly lower inhibition of steroidogenesis and spermatogenesis compared to the wild-type virus in mouse models. These findings enhance our understanding of how ZIKV impacts male reproductive health and provide crucial insights for future preventive and therapeutic strategies.

Date: 2025
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DOI: 10.1038/s41467-025-62044-x

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