a Department of Gastroenterology and Hepatology , Erasmus MC-University Medical Center , Rotterdam , The Netherlands.
b Medical Faculty, Kunming University of Science and Technology , Kunming , P. R. China.
Virulence. 2018 Jan 1;9(1):83-98. doi: 10.1080/21505594.2017.1326443. Epub 2017 Jun 1.
Rotavirus infection is a major cause of severe dehydrating diarrhea in infants younger than 5 y old and in particular cases of immunocompromised patients irrespective to the age of the patients. Although vaccines have been developed, antiviral therapy is an important complement that cannot be substituted. Because of the lack of specific approved treatment, it is urgent to facilitate the cascade of further understanding of the infection biology, identification of druggable targets and the final development of effective antiviral therapies. PI3K-Akt-mTOR signaling pathway plays a vital role in regulating the infection course of many viruses. In this study, we have dissected the effects of PI3K-Akt-mTOR signaling pathway on rotavirus infection using both conventional cell culture models and a 3D model of human primary intestinal organoids. We found that PI3K-Akt-mTOR signaling is essential in sustaining rotavirus infection. Thus, blocking the key elements of this pathway, including PI3K, mTOR and 4E-BP1, has resulted in potent anti-rotavirus activity. Importantly, a clinically used mTOR inhibitor, rapamycin, potently inhibited both experimental and patient-derived rotavirus strains. This effect involves 4E-BP1 mediated induction of autophagy, which in turn exerts anti-rotavirus effects. These results revealed new insights on rotavirus-host interactions and provided new avenues for antiviral drug development.
轮状病毒感染是导致 5 岁以下婴幼儿严重脱水性腹泻的主要原因，在某些免疫功能低下的患者中，无论患者年龄大小，均可发生轮状病毒感染。虽然已经开发出疫苗，但抗病毒治疗是一种重要的补充，不能替代。由于缺乏特定的批准治疗方法，迫切需要促进对感染生物学的进一步理解、鉴定可用药靶以及最终开发有效的抗病毒治疗方法的级联反应。PI3K-Akt-mTOR 信号通路在调节许多病毒的感染过程中起着至关重要的作用。在这项研究中，我们使用传统的细胞培养模型和人类原代肠类器官的 3D 模型，剖析了 PI3K-Akt-mTOR 信号通路对轮状病毒感染的影响。我们发现，PI3K-Akt-mTOR 信号通路对于维持轮状病毒感染是必不可少的。因此，阻断该通路的关键要素，包括 PI3K、mTOR 和 4E-BP1，可产生强大的抗轮状病毒活性。重要的是，一种临床使用的 mTOR 抑制剂雷帕霉素能有效抑制实验和患者来源的轮状病毒株。这种作用涉及到 4E-BP1 介导的自噬诱导，进而发挥抗轮状病毒作用。这些结果揭示了轮状病毒-宿主相互作用的新见解，并为抗病毒药物的开发提供了新途径。
