Yang Wei, Li Hanyu, Wang Shanshan, Huang Rui, Zhang Yifei, Guo Moujian, Huang Li, Li Shihua, Yang Ruirui, Zhao Dingran, Xiong Yuxin, Liu Yifei, Huang Mengjing, Hui Lixia, Xiao Wei, Wu Ying
State Key Laboratory of Virology and Biosafety and Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan, China.
Research Center for Medicine and Structural Biology, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan, China.
Nat Commun. 2025 Jul 22;16(1):6756. doi: 10.1038/s41467-025-62044-x.
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.
寨卡病毒（ZIKV）感染与睾丸损伤和异常精子发生有关。然而，这些致病过程背后的分子机制仍不清楚。在此，我们证明ZIKV破坏了睾丸间质细胞产生睾酮的能力，导致精子数量减少和活力下降。具体而言，ZIKV的非结构蛋白NS2A通过直接结合睾酮合成中的关键酶CYP17A1的mRNA来下调睾酮的产生，从而抑制其翻译。值得注意的是，NS2A的唯一跨膜片段及其侧翼环对于与CYP17A1 mRNA的这种相互作用至关重要。在该序列内的扫描诱变研究确定了对NS2A结合和CYP17A1 mRNA翻译抑制至关重要的氨基酸残基。睾丸接种携带ZIKV-NS2A或其突变体的腺相关病毒（AAV）表明，单独的ZIKV-NS2A就足以在体内影响类固醇生成和精子发生。此外，通过反向遗传学产生的一种突变病毒，含有一个消除NS2A与CYP17A1 mRNA结合的单氨基酸突变，在小鼠模型中与野生型病毒相比，对类固醇生成和精子发生的抑制作用明显较低。这些发现加深了我们对ZIKV如何影响男性生殖健康的理解，并为未来的预防和治疗策略提供了关键见解。
