Inhibitory effects of bile acids and synthetic farnesoid X receptor agonists on rotavirus replication.

Abstract

Rotaviruses (group A rotaviruses) are the most important cause of severe gastroenteritis in infants and children worldwide. Currently, an antiviral drug is not available and information on therapeutic targets for antiviral development is limited for rotavirus infection. Previously, it was shown that lipid homeostasis is important in rotavirus replication. Since farnesoid X receptor (FXR) and its natural ligands bile acids (such as chenodeoxycholic acid [CDCA]) play major roles in cholesterol and lipid homeostasis, we examined the effects of bile acids and synthetic FXR agonists on rotavirus replication in association with cellular lipid levels. In a mouse model of rotavirus infection, effects of oral administration of CDCA on fecal rotavirus shedding were investigated. The results demonstrate the following. First, the intracellular contents of triglycerides were significantly increased by rotavirus infection. Second, CDCA, deoxycholic acid (DCA), and other synthetic FXR agonists, such as GW4064, significantly reduced rotavirus replication in cell culture in a dose-dependent manner. The reduction of virus replication correlated positively with activation of the FXR pathway and reduction of cellular triglyceride contents (r(2) = 0.95). Third, oral administration of CDCA significantly reduced fecal virus shedding in mice (P < 0.05). We conclude that bile acids and FXR agonists play important roles in the suppression of rotavirus replication. The inhibition mechanism is proposed to be the downregulation of lipid synthesis induced by rotavirus infection.

• Authors: Yunjeong Kim, Kyeong-Ok Chang
• Journal: Journal of virology (J Virol) Vol. 85 Issue 23 Pg. 12570-7 (Dec 2011) ISSN: 1098-5514 [Electronic] United States
• PMID: 21957312 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Fxr1h protein, mouse
• Gastrointestinal Agents
• Isoxazoles
• RNA, Messenger
• RNA-Binding Proteins
• Triglycerides
• Chenodeoxycholic Acid
• GW 4064

Topics

• Animals
• Blotting, Western
• Caco-2 Cells
• Carcinoma, Hepatocellular (drug therapy, metabolism, virology)
• Chenodeoxycholic Acid (pharmacology)
• Female
• Gastrointestinal Agents (pharmacology)
• Humans
• Isoxazoles (pharmacology)
• Liver Neoplasms (drug therapy, metabolism, virology)
• Mice
• Mice, Inbred BALB C
• RNA, Messenger (genetics)
• RNA-Binding Proteins (agonists)
• Real-Time Polymerase Chain Reaction
• Rotavirus (drug effects, growth & development)
• Rotavirus Infections (drug therapy, metabolism, virology)
• Triglycerides (metabolism)
• Tumor Cells, Cultured
• Virus Replication (drug effects)