PMID- 35758658
OWN - NLM
STAT- MEDLINE
DCOM- 20220729
LR  - 20220824
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Print)
IS  - 0022-538X (Linking)
VI  - 96
IP  - 14
DP  - 2022 Jul 27
TI  - PRRSV Infection Induces Gasdermin D-Driven Pyroptosis of Porcine Alveolar 
      Macrophages through NLRP3 Inflammasome Activation.
PG  - e0212721
LID - 10.1128/jvi.02127-21 [doi]
LID - e02127-21
AB  - 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-1beta 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.
FAU - He, Sheng
AU  - He S
AUID- ORCID: 0000-0002-3047-5272
AD  - State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen 
      Universitygrid.12981.33, Guangzhou Higher Education Mega Center, Guangzhou, 
      Guangdong, People's Republic of China.
FAU - Li, Lu
AU  - Li L
AD  - State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen 
      Universitygrid.12981.33, Guangzhou Higher Education Mega Center, Guangzhou, 
      Guangdong, People's Republic of China.
FAU - Chen, Haifan
AU  - Chen H
AD  - State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen 
      Universitygrid.12981.33, Guangzhou Higher Education Mega Center, Guangzhou, 
      Guangdong, People's Republic of China.
FAU - Hu, Xiaoli
AU  - Hu X
AD  - State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen 
      Universitygrid.12981.33, Guangzhou Higher Education Mega Center, Guangzhou, 
      Guangdong, People's Republic of China.
FAU - Wang, Wendi
AU  - Wang W
AD  - State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen 
      Universitygrid.12981.33, Guangzhou Higher Education Mega Center, Guangzhou, 
      Guangdong, People's Republic of China.
FAU - Zhang, Hui
AU  - Zhang H
AD  - State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen 
      Universitygrid.12981.33, Guangzhou Higher Education Mega Center, Guangzhou, 
      Guangdong, People's Republic of China.
FAU - Wei, Ruiping
AU  - Wei R
AD  - State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen 
      Universitygrid.12981.33, Guangzhou Higher Education Mega Center, Guangzhou, 
      Guangdong, People's Republic of China.
FAU - Zhang, Xiaoxiao
AU  - Zhang X
AD  - State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen 
      Universitygrid.12981.33, Guangzhou Higher Education Mega Center, Guangzhou, 
      Guangdong, People's Republic of China.
FAU - Chen, Yaosheng
AU  - Chen Y
AD  - State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen 
      Universitygrid.12981.33, Guangzhou Higher Education Mega Center, Guangzhou, 
      Guangdong, People's Republic of China.
FAU - Liu, Xiaohong
AU  - Liu X
AD  - State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen 
      Universitygrid.12981.33, Guangzhou Higher Education Mega Center, Guangzhou, 
      Guangdong, People's Republic of China.
LA  - eng
PT  - Journal Article
DEP - 20220627
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (Inflammasomes)
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - 0 (Pore Forming Cytotoxic Proteins)
SB  - IM
MH  - Animals
MH  - Female
MH  - *Inflammasomes/metabolism
MH  - *Macrophages, Alveolar/pathology
MH  - NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism
MH  - *Porcine Reproductive and Respiratory Syndrome/physiopathology
MH  - *Porcine respiratory and reproductive syndrome virus/metabolism
MH  - *Pore Forming Cytotoxic Proteins/metabolism
MH  - *Pyroptosis/physiology
MH  - Swine
PMC - PMC9327688
OTO - NOTNLM
OT  - NLRP3 inflammasome
OT  - dispersed trans-Golgi network
OT  - porcine reproductive and respiratory syndrome virus
OT  - pyroptosis
OT  - replication-transcription complex
COIS- The authors declare no conflict of interest.
EDAT- 2022/06/28 06:00
MHDA- 2022/07/30 06:00
PMCR- 2022/06/27
CRDT- 2022/06/27 09:04
PHST- 2022/06/28 06:00 [pubmed]
PHST- 2022/07/30 06:00 [medline]
PHST- 2022/06/27 09:04 [entrez]
PHST- 2022/06/27 00:00 [pmc-release]
AID - 02127-21 [pii]
AID - jvi.02127-21 [pii]
AID - 10.1128/jvi.02127-21 [doi]
PST - ppublish
SO  - J Virol. 2022 Jul 27;96(14):e0212721. doi: 10.1128/jvi.02127-21. Epub 2022 Jun 
      27.