Porcine Reproductive and Respiratory Syndrome Virus Induces Interleukin-15 through the NF-κB Signaling Pathway

Zhu

et al. 2017

J Virol

Porcine reproductive and respiratory syndrome virus (PRRSV) continues to cause substantial economic losses to the pig industry worldwide. Heparan sulfate (HS) is used by PRRSV for initial attachment to target cells. However, the role of HS in the late phase of PRRSV infection and the mechanism of virus release from host cells remain largely unknown. In this study, we showed that PRRSV infection caused a decrease in HS expression and upregulated heparanase, the only known enzyme capable of degrading HS. We subsequently demonstrated that the NF-B signaling pathway and cathepsin L protease were involved in regulation of PRRSV infectioninduced heparanase. In addition, we found that ablation of heparanase expression using small interfering RNA duplexes increased cell surface expression of HS and suppressed PRRSV replication and release, whereas overexpression of heparanase reduced HS surface expression and enhanced PRRSV replication and release. These data suggest that PRRSV activates NF-B and cathepsin L to upregulate and process heparanase, and then the active heparanase cleaves HS, resulting in viral release. Our findings provide new insight into the molecular mechanism of PRRSV egress from host cells, which might help us to further understand PRRSV pathogenesis.IMPORTANCE Porcine reproductive and respiratory syndrome virus (PRRSV) causes great economic losses each year to the pig industry worldwide. The molecular mechanism of PRRSV release from host cells largely remains a mystery. In this study, we demonstrate that PRRSV activates NF-B and cathepsin L to upregulate and process heparanase, and then the active heparanase is released to the extracellular space and exerts enzymatic activity to cleave heparan sulfate, resulting in viral release. Our findings provide new insight into the molecular mechanism of PRRSV egress from host cells, which might help us to further understand PRRSV pathogenesis.KEYWORDS PRRSV, heparan sulfate, heparanase, viral release, porcine reproductive and respiratory syndrome virus P orcine reproductive and respiratory syndrome (PRRS) has become one of the most important diseases of intensive pig production worldwide since its emergence in the late 1980s (1, 2). This disease is characterized by respiratory disease, weight loss, and poor growth performance, as well as by late-term abortions (3). The causative agent, PRRS virus (PRRSV), is a small, enveloped, positive-sense, single-stranded RNA virus of the genus Arterivirus, in the family Arteriviridae within the order Nidovirales (4, 5). The PRRSV genome is approximately 15 kb in length and consists of at least 12 overlapping open reading frames (6, 7). Due to the genetic and antigenic differences, PRRSV can be divided into European genotype 1 and North American genotype 2, with Lelystad and VR-2332 as prototypical strains, respectively, which share about 60% nucleotide sequence identity (8). In 2006, highly pathogenic PRRSV (HP-PRRSV)

Section: Resultsmentioning

confidence: 99%

Heparanase Upregulation Contributes to Porcine Reproductive and Respiratory Syndrome Virus Release

Zhu

et al. 2017

J Virol

The Journal of Immunology

“…1G), suggesting that NF-kB binding site 1 is critical for the upregulation of pri-miR-30c-2 by PRRSV. NF-kB can be activated by PRRSV infection (40). To investigate whether the activation of NF-kB is coincident with miR-30c induction, we performed a time-course analysis to determine the activation of NF-kB in PRRSV-infected cells.…”

Section: Mir-30c Is Upregulated By Prrsv Through Activating Nf-kbmentioning

confidence: 99%

MicroRNA-30c Modulates Type I IFN Responses To Facilitate Porcine Reproductive and Respiratory Syndrome Virus Infection by Targeting JAK1

Zhang

Huang

Yang

et al. 2016

Self Cite

Porcine reproductive and respiratory syndrome virus (PRRSV) is an economically important pathogen and has evolved several mechanisms to evade IFN-I responses. We report that a host microRNA, miR-30c, was upregulated by PRRSV via activating NF-κB and facilitated its ability to infect subject animals. Subsequently, we demonstrated that miR-30c was a potent negative regulator of IFN-I signaling by targeting JAK1, resulting in the enhancement of PRRSV infection. In addition, we found that JAK1 expression was significantly decreased by PRRSV and recovered when miR-30c inhibitor was overexpressed. Importantly, miR-30c was also upregulated by PRRSV infection in vivo, and miR-30c expression corresponded well with viral loads in lungs and porcine alveolar macrophages of PRRSV-infected pigs. Our findings identify a new strategy taken by PRRSV to escape IFN-I–mediated antiviral immune responses by engaging miR-30c and, thus, improve our understanding of its pathogenesis.

“…Our previous work shows that PRRSV induces IL-15 production through NF-κB signaling pathway (Fu et al, 2012). However, the mechanism about how PRRSV activates NF-κB to up-regulate IL-15 is not complete.…”

Section: Introductionmentioning

confidence: 99%

“…PRRSV infection triggers the altered expression of many cytokines including the up-regulation of IL-15 Fu et al, 2012;Hou et al, 2012;Huang et al, 2014). IL-15 is a pleiotropic cytokine that is classified into 4α-helix bundle cytokine family (Tagaya et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Porcine reproductive and respiratory syndrome virus (PRRSV) up-regulates IL-15 through PKCβ1-TAK1-NF-κB signaling pathway

Liu

et al. 2016

Virology

Self Cite

Porcine reproductive and respiratory syndrome (PRRS) caused by PRRS virus (PRRSV) is one of the most important infectious diseases in swine industry. IL-15 is a pleiotropic cytokine and has been shown to be essential to transform NKs, CD8 T cells, and other cells of the immune systems into functional effectors. Here, we demonstrated that the broad-spectrum or conventional PKC inhibitors repressed PRRSV-induced IL-15 expression and NF-κB activation. Subsequently, we found that the PKCβ specific inhibitor inhibited PRRSV-induced IL-15 production, which was also confirmed by knock-down of PKCβ1, suggesting that PKCβ1 is involved in the PRRSV-induced IL-15 expression. In addition, we demonstrated that PRRSV activated NF-κB through PKCβ1-induced TAK1 activation. Finally, we demonstrated that PRRSV activated PKCβ1 dependent on the participation of TRIF and MAVS. These data indicate that PRRSV up-regulates IL-15 through TRIF/MAVS-PKCβ1-TAK1-NF-κB signaling pathway. These findings will provide new insights into the molecular mechanisms of IL-15 production induced by PRRSV.