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Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus Induces Interleukin-17 Production via Activation of the IRAK1-PI3K-p38MAPK-C/EBP?/CREB Pathways.

ABSTRACT: 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/EBP? and CREB binding motif in porcine IL-17 promoter abrogated its activation and that knockdown of C/EBP? and CREB remarkably impaired PRRSV-induced IL-17 production, suggesting that IL-17 expression was dependent on C/EBP? and CREB. More specifically, we demonstrate that PRRSV nonstructural protein 11 (nsp11) induced IL-17 production, which was also dependent on PI3K-p38MAPK-C/EBP?/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-PRRSV in 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.IMPORTANCE Highly 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.

SUBMITTER: Wang H

PROVIDER: S-EPMC6803251 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus Induces Interleukin-17 Production via Activation of the IRAK1-PI3K-p38MAPK-C/EBPβ/CREB Pathways.

Wang Honglei H Du Li L Liu Fang F Wei Zeyu Z Gao Li L Feng Wen-Hai WH

Journal of virology 20191015 21

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 dramatic ...[more]

PMID: 31413135

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Project description:Monocyte chemotactic protein-induced protein 1 (MCPIP1) is an inflammatory regulator in immune response and has broad antiviral effects by targeting viral RNA. Porcine reproductive and respiratory syndrome virus (PRRSV), a major viral pathogen in pigs, causes immune suppression leading to coinfection of swine pathogens, but the mechanisms are not fully clarified. In this study, MCPIP1 expression was found to be significantly upregulated in lungs of PRRSV-infected piglets, as well as in Marc-145 and porcine pulmonary alveolar macrophage (PAM) cells upon PRRSV stimulation. MCPIP1 overexpression significantly inhibited PRRSV replication, while MCPIP1 knockdown increased the virus titer. Various mutations in RNase functional domains of MCPIP1 impaired the inhibitory activity against PRRSV, while those in deubiquitinase domains failed to do so. MCPIP1 expression started to decrease from 60 h after PRRSV infection in PAMs. Meanwhile, infection with higher dose of PRRSV further downregulated MCPIP1, indicating the antagonizing effects from PRRSV against MCPIP1. Moreover, it was confirmed that MCPIP1 expression was downregulated in 3D4 cells with either interleukin-17 (IL-17) or nsp11 overexpression, while IL-17 inhibitor abolished the decrease of MCPIP1 caused by nsp11, indicating nsp11 employs IL-17 induction to inhibit MCPIP1. Furthermore, the PRRSV nsp11 mutant with a deficiency in IL-17 induction showed the recovered expression of MCPIP1 in infected cells, inspiring a strategy for virus attenuation. This is the first report about the role of MCPIP1 against PRRSV and the function of PRRSV nsp11 against innate immunity to facilitate virus replication via IL-17. The study not only illuminates PRRSV infection machinery but also enlightens alternative antiviral strategies, such as vaccine candidates. IMPORTANCE Porcine reproductive and respiratory syndrome virus (PRRSV) suppresses the innate immunity and leads to coinfection of swine pathogens. Monocyte chemotactic protein-induced protein 1 (MCPIP1) is a broad-spectrum host antiviral protein. Therefore, to further clarify the mechanism of PRRSV against innate immunity, we explored the relationship between MCPIP1 and PRRSV infection. The results showed that MCPIP1 inhibited PRRSV infection in the early stage of virus infection. Importantly, PRRSV nsp11 subsequently employed IL-17 induction to suppress MCPIP1 expression and antagonized anti-PRRSV effects. Furthermore, PRRSV with mutation of nsp11 S74A failed to induce MCPIP1 reduction. These findings confirmed the function of MCPIP1 against PRRSV and revealed that PRRSV nsp11 plays an important role in virus against innate immunity. This study enlightens a new strategy to develop safer attenuated vaccines against PRRSV by nsp11 mutation.

Project description:BackgroundPorcine reproductive and respiratory syndrome virus (PRRSV) is the causative agent of porcine reproductive and respiratory syndrome (PRRS) and porcine circovirus type 2 (PCV2) is associated with postweaning multisystemic wasting syndrome (PMWS) in pigs. Coinfection with highly pathogenic PRRSV (HP-PRRSV) and PCV2 in the field has recently become extensive in some Asian countries. A synergistic pathogenicity between PRRSV and PCV2 infections has previously been reported. However, the consequences of the sequential infection of pigs with these two viruses are unknown.MethodsThirty 35-day-old piglets were randomly divided into six groups (n = 5 each): HP-PRRSV/PCV2 (group 1, inoculated with HP-PRRSV, then inoculated with PCV2 one week later), PCV2/HP-PRRSV (group 2, inoculated with PCV2, then inoculated with HP-PRRSV one week later), HP-PRRSV+PCV2 (group 3, inoculated with HP-PRRSV and PCV2 concurrently), HP-PRRSV (group 4, inoculated with HP-PRRSV), PCV2 (group 5, inoculated with PCV2), and the control (group 6, uninfected). This experiment lasted 28 days. Clinical symptoms and rectal temperatures were recorded each day after inoculation, body weight was recorded weekly, and serum samples were obtained for viral nucleic acid quantification and antibody titration. Variations in CD3+, CD4+ CD8-, CD3+, CD4-, and CD8+ cells, natural killer (NK) cells, and mononuclear cells were determined by flow cytometry. The serum concentrations of interferon γ (IFN-γ), tumor necrosis factor α (TNF-α), interleukin 10 (IL-10), and macrophage granulocyte-colony stimulating factor (GM-CSF) were determined. Pathological changes in different tissues from the experimentally infected pigs were recorded.ResultsThe piglets in group 1 had the highest viral loads, the lowest antibody titers, the most-severe clinical signs, and the highest mortality (3/5, 60%; the mortality in the other groups was 0%), and interstitial pneumonia was more severe in this group compare to the other HP-PRRSV infected groups. The serum levels of IFN-γ, TNF-α, IL-10, and GM-CSF varied (increased or decreased) most widely in group 1, as did each immunocyte subgroup.ConclusionsHP-PRRSV infection followed by PCV2 infection enhanced the replication of both viruses in the experimental piglets and led to more-severe clinical signs and lesions, indicating greater synergistic effects during the sequential infection of piglets with HP-PRRSV and then PCV2.

Dataset Information

Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus Induces Interleukin-17 Production via Activation of the IRAK1-PI3K-p38MAPK-C/EBP?/CREB Pathways.

Publications

Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus Induces Interleukin-17 Production via Activation of the IRAK1-PI3K-p38MAPK-C/EBPβ/CREB Pathways.

Similar Datasets

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