Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus Induces Interleukin-17 Production via Activation of the IRAK1-PI3K-p38MAPK-C/EBP ? /CREB Pathways
Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus Induces Interleukin-17 Production via Activation of the IRAK1-PI3K-p38MAPK-C/EBP ? /CREB Pathways
复制标题
高致病性猪繁殖与呼吸综合征病毒通过激活 IRAK1-PI3K-p38MAPK-C/EBP 诱导白细胞介素 17 产生？
DOI：
10.1128/jvi.01100-19
复制
发表时间：
2019
影响因子：
5.4
通讯作者：
Wen-hai Feng
中科院分区：
文献类型：
--
作者：
Honglei Wang;Li Du;Fang Liu;Zeyu Wei;Li Gao;Wen-hai Feng
猪繁殖与呼吸综合征病毒（PRRSV）在猪群中广泛流行，在世界范围内造成重大经济损失。PRRSV感染的一个显著影响是严重肺炎。在本研究中，我们发现白细胞介素-17 （IL-17）在PRRSV感染后上调。随后，我们证明PI3K和p38MAPK信号通路对于prrsv诱导的IL-17产生至关重要，因为添加磷脂酰肌醇3-激酶（PI3K）和p38MAPK抑制剂可显著降低IL-17的产生。此外，我们在这里发现，删除猪IL-17启动子中的C/EBPβ和CREB结合基序可以消除其激活，并且敲低C/EBPβ和CREB显著损害了prrsv诱导的IL-17的产生，这表明IL-17的表达依赖于C/EBPβ和CREB。更具体地说，我们证明了PRRSV非结构蛋白11 （nsp11）诱导IL-17的产生，IL-17也依赖于PI3K-p38MAPK-C/EBPβ/CREB途径。然后我们发现Ser74和Phe76氨基酸是nsp11诱导IL-17产生和病毒拯救所必需的。此外，nsp11需要IRAK1通过相互作用激活PI3K并增强IL-17的表达。重要的是，我们证明PI3K抑制剂在体内显著抑制IL-17的产生和HP-PRRSV引起的肺部炎症，这意味着HP-PRRSV诱导的IL-17水平升高可能与严重的肺部炎症有关。这些发现为PRRSV诱导IL-17产生的分子机制提供了新的见解，有助于我们进一步了解PRRSV感染的发病机制。与严重肺炎相关的高致病性猪繁殖与呼吸综合征病毒（HP-PRRSV）是猪中最重要的病毒性病原体之一。IL-17是一种促炎细胞因子，可能与PRRSV引起的强烈炎症有关。因此，我们试图确定PRRSV感染是否影响IL-17的表达，如果是，确定这可能部分解释hp -PRRSV感染猪的强烈炎症的潜在机制，特别是在肺部。在这里，我们发现PRRSV显著诱导IL-17表达，我们随后解剖了PRRSV如何调节IL-17产生的分子机制。此外，我们发现nsp11中的Ser74和Phe76对于IL-17的产生和病毒复制是不可或缺的。重要的是，我们证明了PI3K抑制剂会破坏IL-17的产生，并减轻HP-PRRSV感染引起的肺部炎症。我们的发现将有助于我们更好地了解PRRSV的发病机制。
Porcine reproductive and respiratory syndrome virus (PRRSV) is widely prevalent in pigs, resulting in significant economic losses worldwide. A compelling impact of PRRSV infection is severe pneumonia. In the present study, we found that interleukin-17 (IL-17) was upregulated by PRRSV infection. Subsequently, we demonstrated that PI3K and p38MAPK signaling pathways were essential for PRRSV-induced IL-17 production as addition of phosphatidylinositol 3-kinase (PI3K) and p38MAPK inhibitors dramatically reduced IL-17 production. Furthermore, we show here that deleting the C/EBPβ and CREB binding motif in porcine IL-17 promoter abrogated its activation and that knockdown of C/EBPβ and CREB remarkably impaired PRRSV-induced IL-17 production, suggesting that IL-17 expression was dependent on C/EBPβ and CREB. More specifically, we demonstrate that PRRSV nonstructural protein 11 (nsp11) induced IL-17 production, which was also dependent on PI3K-p38MAPK-C/EBPβ/CREB pathways. We then show that Ser74 and Phe76 amino acids were essential for nsp11 to induce IL-17 production and viral rescue. In addition, IRAK1 was required for nsp11 to activate PI3K and enhance IL-17 expression by interacting with each other. Importantly, we demonstrate that PI3K inhibitor significantly suppressed IL-17 production and lung inflammation caused by HP-PRRSVin vivo, implicating that higher IL-17 level induced by HP-PRRSV might be associated with severe lung inflammation. These findings provide new insights onto the molecular mechanisms of the PRRSV-induced IL-17 production and help us further understand the pathogenesis of PRRSV infection.IMPORTANCEHighly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) associated with severe pneumonia has been one of the most important viral pathogens in pigs. IL-17 is a proinflammatory cytokine that might be associated with the strong inflammation caused by PRRSV. Therefore, we sought to determine whether PRRSV infection affects IL-17 expression, and if so, determine this might partially explain the underlying mechanisms for the strong inflammation in HP-PRRSV-infected pigs, especially in lungs. Here, we show that PRRSV significantly induced IL-17 expression, and we subsequently dissected the molecular mechanisms about how PRRSV regulated IL-17 production. Furthermore, we show that Ser74 and Phe76 in nsp11 were indispensable for IL-17 production and viral replication. Importantly, we demonstrated that PI3K inhibitor impaired IL-17 production and alleviated lung inflammation caused by HP-PRRSV infection. Our findings will help us for a better understanding of PRRSV pathogenesis.