Center for Public Health Research, Medical School, Nanjing University, Nanjing, 210093, China.
Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, PR China.
Stem Cell Res Ther. 2024 Nov 19;15(1):435. doi: 10.1186/s13287-024-04040-4.
Zika virus (ZIKV) primarily spreads through mosquito bites and can lead to microcephaly in infants and Guillain-Barre syndrome in adults. It is noteworthy that ZIKV can persist in the semen of infected males for extended periods and can be sexually transmitted. Infection with ZIKV has severe pathological manifestations on the testicular tissues of male mice, resulting in reduced sperm motility and fertility. However, there are no approved prophylactic vaccines or therapeutics available to treat Zika virus infection.
Using a male type I and II interferon receptor-deficient (ifnar1(-/-) ifngr1(-/-)) C57BL/6 (AG6) mouse model infected with ZIKV as a representative model, we evaluated the degree of testicular damage and viral replication in various organs in mice treated with EVs derived from MSC-stimulated with IFN-β (IFNβ-EVs) and treated with controls. We measured testicle size, detected viral load in various organs, and analyzed gene expression to assess treatment efficacy.
Our findings demonstrated that intravenous administration of IFNβ-EVs effectively suppressed ZIKV replication in the testes. Investigation with in-depth RNA sequencing analysis found that IFN-β treatment changed the cargo miRNA of EVs. Notably, miR-431-5p was identified to be significantly enriched in IFNβ-EVs and exhibited potent antiviral activity in vitro. We showed that CD95 was a direct downstream target for miR-431-5p and played a role in facilitating ZIKV replication. miR-431-5p effectively downregulated the expression of CD95 protein, consequently promoted the phosphorylation and nuclear localization of NF-kB, which resulted in the activation of anti-viral status, leading to the suppression of viral replication.
Our study demonstrated that the EVs produced by IFNβ-treated MSCs could effectively convey antiviral activity.
寨卡病毒（ZIKV）主要通过蚊子叮咬传播，可导致婴儿小头畸形和成人格林-巴利综合征。值得注意的是，感染 ZIKV 的男性精液中可长时间存在病毒，并可通过性传播。ZIKV 感染会导致雄性小鼠睾丸组织出现严重的病理表现，导致精子活力和生育能力下降。然而，目前尚无批准的预防疫苗或治疗方法可用于治疗寨卡病毒感染。
我们使用雄性 I 型和 II 型干扰素受体缺陷（ifnar1(-/-) ifngr1(-/-)）C57BL/6（AG6）小鼠感染 ZIKV 作为代表性模型，评估了用 IFN-β 刺激 MSC 衍生的 EV（IFNβ-EVs）和对照处理的小鼠中各种器官的睾丸损伤和病毒复制程度。我们测量了睾丸大小，检测了各种器官中的病毒载量，并分析了基因表达以评估治疗效果。
我们的研究结果表明，静脉注射 IFNβ-EVs 可有效抑制 ZIKV 在睾丸中的复制。通过深入的 RNA 测序分析发现，IFN-β 处理改变了 EV 的 cargo miRNA。值得注意的是，miR-431-5p 在 IFNβ-EVs 中显著富集，并在体外表现出强大的抗病毒活性。我们表明，CD95 是 miR-431-5p 的直接下游靶标，在促进 ZIKV 复制中发挥作用。miR-431-5p 可有效下调 CD95 蛋白的表达，从而促进 NF-kB 的磷酸化和核定位，导致抗病毒状态的激活，从而抑制病毒复制。
我们的研究表明，IFNβ 处理的 MSC 产生的 EV 可有效传递抗病毒活性。
