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

Intranasal Delivery of Inactivated Influenza Virus and Poly(I:C) Adsorbed Corn-Based Nanoparticle Vaccine Elicited Robust Antigen-Specific Cell-Mediated Immune Responses in Maternal Antibody Positive Nursery Pigs

“…There are several reports documenting an increased population of IL-17A producing T cells and secretion of IL-17A in pigs, such as the presence of Actinobacillus pleuropneumoniae specific Th17 cells [CD4 + CD8α dim IL-17A + ] in the blood and lungs of porcine contagious pleuropneumonia infected pigs ( 39 ). IL-17 is a proinflammatory cytokine, likely associated with inflammation in the lungs of pigs infected with Porcine Reproductive and Respiratory Syndrome Virus (PRRSV), because in the serum and BAL fluid of highly pathogenic PRRSV infected pigs IL-17A was detected, and in PRRSV infected alveolar macrophages in vitro high levels of IL-17A gene expression was observed ( 40 ). The presence of enhanced IL-17A producing cells in PBMCs was detected following PMA and ionomycin activation in vitro ( 41 ).…”

The Function of the PRRSV–Host Interactions and Their Effects on Viral Replication and Propagation in Antiviral Strategies

“…Similarly, nsp1 can increase the level of IL-10 as an inducer in vivo [ 35 ]. IL-17 is a proinflammatory cytokine associated with intense inflammation and is upregulated by HP-PRRSV of genotype 2 infection [ 13 , 37 ]. A study found that HP-PRRSV nsp11 could induce IL-17 production depending on the phosphatidylinositol 3-kinase (PI3K)-p38MAPK-C/EBPβ/CREB pathways [ 37 ].…”

Escherichia coli Heat-Labile Enterotoxin B Subunit Combined with Ginsenoside Rg1 as an Intranasal Adjuvant Triggers Type I Interferon Signaling Pathway and Enhances Adaptive Immune Responses to an Inactivated PRRSV Vaccine in ICR Mice

“…Porcine reproductive and respiratory syndrome (PRRS) is one of the most severe swine diseases, characterized by reproductive failure in sows and respiratory disease in pigs of all ages [ 1 , 2 ]. The pathogenic agent is porcine reproductive and respiratory syndrome virus (PRRSV), which is an enveloped, positive-strand RNA virus of the family Arteriviridae [ 3 ]. PRRSV infection is highly restricted to cells in the monocyte/macrophage lineage such as porcine alveolar macrophages (PAMs), which are the primary targets of PRRSV in vivo [ 4 ].…”