Porcine Reproductive and Respiratory Syndrome Virus Activates Lipophagy To Facilitate Viral Replication through Downregulation of NDRG1 Expression

Abstract

Autophagy maintains cellular homeostasis by degrading organelles, proteins, and lipids in lysosomes. Autophagy is involved in the innate and adaptive immune responses to a variety of pathogens. Some viruses can hijack host autophagy to enhance their replication. However, the role of autophagy in porcine reproductive and respiratory syndrome virus (PRRSV) infection is unclear. Here, we show that N-Myc downstream-regulated gene 1 (NDRG1) deficiency induced autophagy, which facilitated PRRSV replication by regulating lipid metabolism. NDRG1 mRNA is expressed ubiquitously in most porcine tissues and most strongly in white adipose tissue. PRRSV infection downregulated the expression of NDRG1 mRNA and protein, while NDRG1 deficiency contributed to PRRSV RNA replication and progeny virus assembly. NDRG1 deficiency reduced the number of intracellular lipid droplets (LDs), but the expression levels of key genes in lipogenesis and lipolysis were not altered. Our results also show that NDRG1 deficiency promoted autophagy and increased the subsequent yields of hydrolyzed free fatty acids (FFAs). The reduced LD numbers, increased FFA levels, and enhanced PRRSV replication were abrogated in the presence of an autophagy inhibitor. Overall, our findings suggest that NDRG1 plays a negative role in PRRSV replication by suppressing autophagy and LD degradation. IMPORTANCE Porcine reproductive and respiratory syndrome virus (PRRSV), an enveloped single-positive-stranded RNA virus, causes acute respiratory distress in piglets and reproductive failure in sows. It has led to tremendous economic losses in the swine industry worldwide since it was first documented in the late 1980s. Vaccination is currently the major strategy used to control the disease. However, conventional vaccines and other strategies do not provide satisfactory or sustainable prevention. Therefore, safe and effective strategies to control PRRSV are urgently required. The significance of our research is that we demonstrate a previously unreported relationship between PRRSV, NDRG1, and lipophagy in the context of viral infection. Furthermore, our data point to a new role for NDRG1 in autophagy and lipid metabolism. Thus, NDRG1 and lipophagy will have significant implications for understanding PRRSV pathogenesis for developing new therapeutics.

Identification of Immune Response to Sacbrood Virus Infection in Apis cerana Under Natural Condition

“…However, metabolites are another important indicator that can reflect physiological response to pathogens (Marelli-Berg et al, 2012). Fatty acid metabolism and biosynthesis are known to play a vital role in viral infections and proliferation (Fritsch and Weichhart, 2016;Wang et al, 2019). It has reported that fatty acids can influence host immune by affecting the inflammatory repertoire of the host, substrates for biosynthesis of inflammatory mediators and activation of cell receptors (Huang et al, 2012).…”

Improvement of muscular atrophy by AAV–SaCas9-mediated myostatin gene editing in aged mice

“…Procedures were carried out as previously described [ 19 ]. Protein extracts were prepared on ice by homogenizing pieces of frozen tissues or cell pellets in 500 µl of RIPA Lysis Buffer (50 mM Tris-HCl, pH 8.0, 150 mM NaCl, 1% Triton X-100, 1% sodium deoxycholate, 0.1% SDS, 2 mM MgCl 2 ) supplemented with 1:100 protease inhibitor solution (Roche, Basel, Swiss) by syringe blowing.…”

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

“…Upon internalization with the participation of pSn, the genome of the virus that is present in the early endosome is released into the cytoplasm [ 53 ]. The last stage is critically dependent on CD163, a scavenger receptor cysteine-rich (SRCR) family for hemoglobin clearance, which is the most specific and indispensable receptor for PRRSV entry and infection both in vitro and in vivo [ 8 , 12 , 59 ]. Additionally, the viral GP2 and GP4 glycoproteins bind to CD163 [ 13 ].…”

“…Moreover, a study has shown that CD163 interacts with GP3 and GP5 in addition to the known interactions with GP4 and GP2, and co-immunoprecipitation (co-IP) analysis indicated that the SRCR5-domain deletion of CD163 loses its interaction with viral GP2, GP3, and GP5, and thus blocks virus uncoating in the early endosomes [ 17 ]. A growing body of research has also indicated that CD163 plays an essential role in viral uncoating and genome release, and CD163 knockout pigs are resistant to PRRSV infection [ 13 , 59 , 60 , 61 ]. In addition to CD163, cellular proteases, such as the aspartic protease cathepsin E and trypsin-like serine proteases, have been implicated in the uncoating process and subsequent infection [ 62 ].…”