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Published on: May 7, 2012
CD14 facilitates perinatal human cytomegalovirus infection in biliary epithelial cells via CD55
Liang Su1,2, Yan Chen1,3, Ming Fu1,4
1Provincial Key Laboratory of Research in Structure Birth Defect Disease and Department of Pediatric Surgery, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
Background & Aims:
A high human cytomegalovirus (HCMV) infection rate accompanied by an increased level of bile duct damage is observed in the perinatal period. The possible mechanism was investigated.
Methods:
A total of 1,120 HCMV-positive and 9,297 HCMV-negative children were recruited, and depending on age, their liver biochemistry profile was compared. Fetal and infant biliary epithelial cells (F-BECs and I-BECs, respectively) were infected with HCMV, and the differences in cells were revealed by proteomic analysis. Protein-protein interactions were examined by coimmunoprecipitation and mass spectrometry analyses. A murine cytomegalovirus (MCMV) infection model was established to assess treatment effects.
Results:
Perinatal HCMV infection significantly increased the level of bile duct damage. Neonatal BALB/c mice inoculated with MCMV showed obvious inflammation in the portal area with an abnormal bile duct structure. Proteomics analysis showed higher CD14 expression in F-BECs than in I-BECs. CD14 siRNA administration hindered HCMV infection, and CD14-knockout mice showed lower MCMV-induced bile duct damage. HCMV infection upregulated CD55 and poly ADP-ribose polymerase-1 (PARP-1) expression in F-BECs. Coimmunoprecipitation and mass spectrometry analyses revealed formation of the CD14-CD55 complex. siRNA-mediated inhibition of CD55 expression reduced sCD14-promoted HCMV replication in F-BECs. In MCMV-infected mice, anti-mouse CD14 antibody and PARP-1 inhibitor treatment diminished cell death, ameliorated bile duct damage, and reduced mortality.
Conclusions:
CD14 facilitates perinatal HCMV infection in BECs via CD55, and PARP-1-mediated cell death was detected in perinatal cytomegalovirus-infected BECs. These results provide new insight into the treatment of perinatal HCMV infection with bile duct damage.
Impact And Implications:
Perinatal human cytomegalovirus (HCMV) infection is associated with bile duct damage, but the underlying mechanism is still unknown. We discovered that CD14 expression is increased in biliary epithelial cells during perinatal HCMV infection and facilitates viral entry through CD55. We also detected PARP-1-mediated cell death in perinatal HCMV-infected biliary epithelial cells. We showed that blocking CD14 or inhibiting PARP-1 reduced bile duct damage and mortality in a mouse model of murine cytomegalovirus infection. Our findings provide a new insight into therapeutic strategies for perinatal HCMV infection.
Insights
Perinatal human cytomegalovirus (HCMV) infection causes bile duct damage by increasing CD14 expression in biliary cells. Targeting CD14 or PARP-1 offers new therapeutic strategies for this condition.
Area of Science:
- Virology
- Immunology
- Hepatology
Background:
- High human cytomegalovirus (HCMV) infection rates correlate with increased perinatal bile duct damage.
- The precise mechanisms underlying this association remain largely unknown.
Purpose of the Study:
- To investigate the mechanism by which HCMV causes bile duct damage during the perinatal period.
- To identify potential therapeutic targets for HCMV-induced bile duct injury.
Main Methods:
- Comparative analysis of liver biochemistry in HCMV-positive and negative children.
- Proteomic and co-immunoprecipitation analyses of HCMV-infected fetal and infant biliary epithelial cells (F-BECs and I-BECs).
- Establishment of a murine cytomegalovirus (MCMV) infection model for therapeutic assessment.
Main Results:
- Perinatal HCMV infection significantly increased bile duct damage and inflammation in mice.
- Elevated CD14 expression in F-BECs facilitated HCMV infection via CD55.
- HCMV infection upregulated CD55 and PARP-1, leading to cell death.
- Inhibition of CD14 or PARP-1 reduced damage, cell death, and mortality in the mouse model.
Conclusions:
- CD14 and CD55 mediate HCMV entry into perinatal biliary epithelial cells.
- PARP-1-mediated cell death plays a role in HCMV-induced bile duct injury.
- Targeting CD14 and PARP-1 demonstrates therapeutic potential for perinatal HCMV infection with bile duct damage.
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