Rhesus rotavirus VP6 regulates ERK-dependent calcium influx in cholangiocytes.
The Rhesus rotavirus (RRV) induced murine model of biliary atresia (BA) is a useful tool in studying the pathogenesis of this neonatal biliary obstructive disease. In this model, the mitogen associated protein kinase pathway is involved in RRV infection of biliary epithelial cells (cholangiocytes). We hypothesized that extracellular signal-related kinase (ERK) phosphorylation is integral to calcium influx, allowing for viral replication within the cholangiocyte. Utilizing ERK and calcium inhibitors in immortalized cholangiocytes and BALB/c pups, we determined that ERK inhibition resulted in reduced viral yield and subsequent decreased symptomatology in mice. In vitro, the RRV VP6 protein induced ERK phosphorylation, leading to cellular calcium influx. Pre-treatment with an ERK inhibitor or Verapamil resulted in lower viral yields. We conclude that the pathogenesis of RRV-induced murine BA is dependent on the VP6 protein causing ERK phosphorylation and triggering calcium influx allowing replication in cholangiocytes.
Department of Pediatric and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Inna
I
Lobeck
Department of Pediatric and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Bryan
B
Donnelly
Department of Pediatric and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Phylicia
P
Dupree
Department of Pediatric and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Maxime M
MM
Mahe
Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Monica
M
McNeal
Department of Pediatric and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Sujit K
SK
Mohanty
Department of Pediatric and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Electronic address: Greg.Tiao@cchmc.org.
Greg
G
Tiao
D000818:Animals; D000956:Antigens, Viral / Q000235:genetics / Q000378:metabolism*; D001656:Biliary Atresia / Q000201:enzymology / Q000378:metabolism / Q000821:virology*; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism; D036022:Capsid Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D008253:Macaca mulatta; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D012401:Rotavirus / Q000235:genetics / Q000378:metabolism*; D012400:Rotavirus Infections / Q000201:enzymology* / Q000378:metabolism / Q000821:virology*
D000956:Antigens, Viral; D036022:Capsid Proteins; C061332:VP6 protein, Rotavirus; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium
Biliary atresia; Calcium; Cholangiocyte; ERK; MAPK pathway; RRV; Rhesus rotavirus; VP6
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