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Porcine reproductive and respiratory syndrome virus induces IL-1? production depending on TLR4/MyD88 pathway and NLRP3 inflammasome in primary porcine alveolar macrophages.

ABSTRACT: Porcine reproductive and respiratory syndrome virus (PRRSV) is an Arterivirus that has been devastating the swine industry worldwide since the late 1980s. Previous studies have reported that PRRSV infection induced the production of IL-1 ? . However, the cellular sensors and signaling pathways involved in this process have not been elucidated yet. Here, we studied the mechanisms responsible for the production of IL-1 ? in response to highly pathogenic PRRSV. Upon PRRSV infection of primary porcine alveolar macrophages, both mRNA expression and secretion of IL-1 ? were significantly increased in a time- and dose-dependent manner. We also investigated the role of several pattern-recognition receptors and adaptor molecules in this response and showed that the TLR4/MyD88 pathway and its downstream signaling molecules, NF- ? B, ERK1/2, and p38 MAPKs, were involved in IL-1 ? production during PRRSV infection. Treatment with specific inhibitors or siRNA knockdown assays demonstrated that components of the NLRP3 inflammasome were crucial for IL-1 ? secretion but not for IL-1 ? mRNA expression. Furthermore, TLR4/MyD88/NF- ? B signaling pathway was involved in PRRSV-induced expression of NLRP3 inflammasome components. Together, our results deciphered the pathways leading from recognition of PRRSV to the production and release of IL-1 ? , providing a deeper knowledge of the mechanisms of PRRSV-induced inflammation responses.

SUBMITTER: Bi J

PROVIDER: S-EPMC4055429 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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Porcine reproductive and respiratory syndrome virus induces IL-1β production depending on TLR4/MyD88 pathway and NLRP3 inflammasome in primary porcine alveolar macrophages.

Bi Jing J Song Shuang S Fang Liurong L Wang Dang D Jing Huiyuan H Gao Li L Cai Yidong Y Luo Rui R Chen Huanchun H Xiao Shaobo S

Mediators of inflammation 20140521

Porcine reproductive and respiratory syndrome virus (PRRSV) is an Arterivirus that has been devastating the swine industry worldwide since the late 1980s. Previous studies have reported that PRRSV infection induced the production of IL-1 β . However, the cellular sensors and signaling pathways involved in this process have not been elucidated yet. Here, we studied the mechanisms responsible for the production of IL-1 β in response to highly pathogenic PRRSV. Upon PRRSV infection of primary porci ...[more]

PMID: 24966466

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Project description:For more than 3 decades, mounting evidence has associated porcine reproductive and respiratory syndrome virus (PRRSV) infection with late-term abortions and stillbirths in sows and respiratory disease in piglets, causing enormous economic losses to the global swine industry. However, to date, the underlying mechanisms of PRRSV-triggered cell death have not been well clarified, especially in the pulmonary inflammatory injury characterized by the massive release of pro-inflammatory factors. Here, we demonstrated that PRRSV infection triggered gasdermin D-mediated host pyroptosis in vitro and in vivo. Mechanistically, PRRSV infection triggered disassembly of the trans-Golgi network (TGN); the dispersed TGN then acted as a scaffold for NLRP3 activation through phosphatidylinositol-4-phosphate. In addition, PRRSV replication-transcription complex (RTC) formation stimulated TGN dispersion and pyroptotic cell death. Furthermore, our results indicated that TMEM41B, an endoplasmic reticulum (ER)-resident host protein, functioned as a crucial host factor in the formation of PRRSV RTC, which is surrounded by the intermediate filament network. Collectively, these findings uncover new insights into clinical features as previously unrecognized mechanisms for PRRSV-induced pathological effects, which may be conducive to providing treatment options for PRRSV-associated diseases and may be conserved during infection by other highly pathogenic viruses. IMPORTANCE Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the pathogens responsible for major economic losses in the global swine industry. Characterizing the detailed process by which PRRSV induces cell death pathways will help us better understand viral pathogenesis and provide implications for therapeutic intervention against PRRSV. Here, we showed that PRRSV infection induces GSDMD-driven host pyroptosis and IL-1β secretion through NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activation in vitro and in vivo. Furthermore, the molecular mechanisms of PRRSV-induced NLRP3 inflammasome activation and pyroptosis are elucidated here. The dispersed trans-Golgi network (TGN) induced by PRRSV serves as a scaffold for NLRP3 aggregation into multiple puncta via phosphatidylinositol 4-phosphate (PtdIns4P). Moreover, the formation of PRRSV replication-transcription complex is essential for TGN dispersion and host pyroptosis. This research advances our understanding of the PRRSV-mediated inflammatory response and cell death pathways, paving the way for the development of effective treatments for PRRSV diseases.

Project description:Porcine reproductive and respiratory syndrome (PRRS) has devastated pig industries worldwide for many years. It is caused by a small RNA virus (PRRSV), which targets almost exclusively pig monocytes or macrophages. In the present study, five SAGE (serial analysis of gene expression) libraries derived from 0 hour mock-infected and 6, 12, 16 and 24 hours PRRSV-infected porcine alveolar macrophages (PAMs) produced a total 643,255 sequenced tags with 91,807 unique tags. Differentially expressed (DE) tags were then detected using the Bayesian framework followed by gene/mRNA assignment, arbitrary selection and manual annotation, which determined 699 DE genes for reactome analysis. The DAVID, KEGG and REACTOME databases assigned 573 of the DE genes into six biological systems, 60 functional categories and 504 pathways. The six systems are: cellular processes, genetic information processing, environmental information processing, metabolism, organismal systems and human diseases as defined by KEGG with modification. Self-organizing map (SOM) analysis further grouped these 699 DE genes into ten clusters, reflecting their expression trends along these five time points. Based on the number one functional category in each system, cell growth and death, transcription processes, signal transductions, energy metabolism, immune system and infectious diseases formed the major reactomes of PAMs responding to PRRSV infection. Our investigation also focused on dominant pathways that had at least 20 DE genes identified, multi-pathway genes that were involved in 10 or more pathways and exclusively-expressed genes that were included in one system. Overall, our present study reported a large set of DE genes, compiled a comprehensive coverage of pathways, and revealed system-based reactomes of PAMs infected with PRRSV. We believe that our reactome data provides new insight into molecular mechanisms involved in host genetic complexity of antiviral activities against PRRSV and lays a strong foundation for vaccine development to control PRRS incidence in pigs.

Dataset Information

Porcine reproductive and respiratory syndrome virus induces IL-1? production depending on TLR4/MyD88 pathway and NLRP3 inflammasome in primary porcine alveolar macrophages.

Publications

Porcine reproductive and respiratory syndrome virus induces IL-1β production depending on TLR4/MyD88 pathway and NLRP3 inflammasome in primary porcine alveolar macrophages.

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