Abstract
Transmissible gastroenteritis virus (TGEV), a coronavirus, causes severe diarrhea and high mortality in newborn piglets. The porcine intestinal epithelium is the target of TGEV infection, but the mechanisms that TGEV disrupts the actin cytoskeleton and invades the host epithelium remain largely unknown. We not only found that TGEV infection stimulates F-actin to gather at the cell membrane but the disruption of F-actin inhibits TGEV entry as well. Cofilin is involved in F-actin reorganization and TGEV entry. The TGEV spike protein is capable of binding with EGFR, activating the downstream phosphoinositide-3 kinase (PI3K), then causing the phosphorylation of cofilin and F-actin polymerization via Rac1/Cdc42 GTPases. Inhibition of EGFR and PI3K decreases the entry of TGEV. EGFR is also the upstream activator of mitogen-activated protein kinase (MAPK) signaling pathways that is involved in F-actin reorganization. Additionally, lipid rafts act as signal platforms for the EGFR-associated signaling cascade and correlate with the adhesion of TGEV. In conlusion, these results provide valuable data of the mechanisms which are responsible for the TGEV pathogenesis and may lead to the development of new methods about controlling TGEV.
Highlights
Porcine transmissible gastroenteritis virus (TGEV) is an enveloped enteropathogenic coronavirus (CoV) with a large positive-sense single-stranded RNA genome about 28.5 kb in length
We found that Transmissible gastroenteritis virus (TGEV) acted via the EGFRPI3K-Rac1/Cdc42-PAK-LIMK signaling pathway to regulate the activity of cofilin and F-actin arrangement early in infection, and demonstrated that epidermal growth factor receptor (EGFR) was a promoter for TGEV entry
Transmission electron microscopy (TEM) confirmed that F-actin gathered underneath the plasma membrane, the podosome and lamellipodium were observed in the cell membrane (Indicated by the white arrows)
Summary
Porcine transmissible gastroenteritis virus (TGEV) is an enveloped enteropathogenic coronavirus (CoV) with a large positive-sense single-stranded RNA genome about 28.5 kb in length. The CoV spike protein binds to a cellular receptor and mediates membrane fusion at the plasma membrane or by endosomal uptake. TGEV infects epithelial cells through the small intestine and the respiratory tract. The virus enters epithelial cells from the apical or basolateral side, and is released from the apical plasma membrane into the gut lumen, where it propagates efficiently by cell-to-cell spreading [2]. Porcine intestinal columnar epithelial cells (IPEC-J2) offer a practical model for studying porcine enteric pathogens [3]. The precise molecular mechanisms responsible for TGEV entry are largely unknown, and limited informations are available on the cell signaling pathways involved in coronavirus entry via the actin cytoskeleton
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