Basal interferon signaling and therapeutic use of interferons in controlling rotavirus infection in human intestinal cells and organoids.
Basal interferon signaling and therapeutic use of interferons in controlling rotavirus infection in human intestinal cells and organoids.
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DOI：
10.1038/s41598-018-26784-9
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发表时间：
2018-05-29
影响因子：
4.6
通讯作者：
Pan Q
中科院分区：
文献类型：
--
作者：
Hakim MS;Chen S;Ding S;Yin Y;Ikram A;Ma XX;Wang W;Peppelenbosch MP;Pan Q
轮状病毒（RV）主要感染肠细胞，导致严重腹泻，尤其是儿童。众所周知，宿主免疫反应决定病毒感染的结果。感染后，干扰素（ifn）作为对抗病毒的第一个也是主要的抗病毒细胞因子产生。我们发现RV在人肠细胞中主要诱导III型IFN (IFN-λ1)，并在较小程度上诱导I型IFN （IFN-α和IFN-β）。然而，它不产生可检测的IFN蛋白，因此，不足以抑制RV复制。相反，我们揭示了基础IFN信号通过沉默STAT1、STAT2和IRF9基因来限制RV复制的重要作用。此外，外源性IFN处理表明，在人肠道Caco2细胞系和原代肠道类器官中，所有类型的IFN都能抑制RV的复制。在这些模型中，ifn显著上调了一组众所周知的抗病毒ifn刺激基因（ISGs）。重要的是，抑制JAK-STAT级联可消除ifn的ISG诱导和抗rv作用。因此，我们的研究将有助于更好地理解RV-宿主之间复杂的相互作用，并为开发基于干扰素的RV感染治疗方法提供理论依据。
Rotavirus (RV) primarily infects enterocytes and results in severe diarrhea, particularly in children. It is known that the host immune responses determine the outcome of viral infections. Following infections, interferons (IFNs) are produced as the first and the main anti-viral cytokines to combat the virus. Here we showed that RV predominantly induced type III IFNs (IFN-λ1), and to a less extent, type I IFNs (IFN-α and IFN-β) in human intestinal cells. However, it did not produce detectable IFN proteins and thus, was not sufficient to inhibit RV replication. In contrast, we revealed the essential roles of the basal IFN signaling in limiting RV replication by silencing STAT1, STAT2 and IRF9 genes. In addition, exogenous IFN treatment demonstrated that RV replication was able to be inhibited by all types of IFNs, both in human intestinal Caco2 cell line and in primary intestinal organoids. In these models, IFNs significantly upregulated a panel of well-known anti-viral IFN-stimulated genes (ISGs). Importantly, inhibition of the JAK-STAT cascade abrogated ISG induction and the anti-RV effects of IFNs. Thus, our study shall contribute to better understanding of the complex RV-host interactions and provide rationale for therapeutic development of IFN-based treatment against RV infection.
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影响因子：
29.4
作者：
Bass, DM
通讯作者：
Bass, DM
影响因子：
29.4
作者：
Greenberg HB;Estes MK
通讯作者：
Estes MK
DOI：
10.1128/cdli.10.6.995-1001.2003
发表时间：
2003-11-01
期刊：
CLINICAL AND DIAGNOSTIC LABORATORY IMMUNOLOGY
影响因子：
--
作者：
Jiang, B;Snipes-Magaldi, L;Glass, RI
通讯作者：
Glass, RI
影响因子：
5.4
作者：
Cuadras, MA;Feigelstock, DA;Greenberg, HB
通讯作者：
Greenberg, HB
影响因子：
3.7
作者：
Lanata CF;Fischer-Walker CL;Olascoaga AC;Torres CX;Aryee MJ;Black RE;Child Health Epidemiology Reference Group of the World Health Organization and UNICEF
通讯作者：
Child Health Epidemiology Reference Group of the World Health Organization and UNICEF