Hepatitis C virus infects the endothelial cells of the blood-brain barrier

Nicola F. Fletcher, Garrick K. Wilson, Jacinta Murray, Ke Hu, Andrew Lewis, Gary M. Reynolds, Zania Stamataki, Luke W. Meredith, Ian A. Rowe, Guangxiang Luo, Miguel A. Lopezramirez, Thomas F. Baumert, Babette Weksler, Pierreolivier Couraud, Kwang Sik Kim, Ignacio A. Romero, Catherine Jopling, Susan Morgello, Peter Balfe, Jane A. McKeating

Research output: Contribution to journalArticle

Abstract

Background & Aims: Hepatitis C virus (HCV) infection leads to progressive liver disease and is associated with a variety of extrahepatic syndromes, including central nervous system (CNS) abnormalities. However, it is unclear whether such cognitive abnormalities are a function of systemic disease, impaired hepatic function, or virus infection of the CNS. Methods: We measured levels of HCV RNA and expression of the viral entry receptor in brain tissue samples from 10 infected individuals (and 3 uninfected individuals, as controls) and human brain microvascular endothelial cells by using quantitative polymerase chain reaction and immunochemical and confocal imaging analyses. HCV pseudoparticles and cell culturederived HCV were used to study the ability of endothelial cells to support viral entry and replication. Results: Using quantitative polymerase chain reaction, we detected HCV RNA in brain tissue of infected individuals at significantly lower levels than in liver samples. Brain microvascular endothelia and brain endothelial cells expressed all of the recognized HCV entry receptors. Two independently derived brain endothelial cell lines, hCMEC/D3 and HBMEC, supported HCV entry and replication. These processes were inhibited by antibodies against the entry factors CD81, scavenger receptor BI, and claudin-1; by interferon; and by reagents that inhibit NS3 protease and NS5B polymerase. HCV infection promotes endothelial permeability and cellular apoptosis. Conclusions: Human brain endothelial cells express functional receptors that support HCV entry and replication. Virus infection of the CNS might lead to HCV-associated neuropathologies.

Original languageEnglish (US)
Pages (from-to)634-643
Number of pages10
JournalGastroenterology
Volume142
Issue number3
DOIs
StatePublished - Mar 2012

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Blood-Brain Barrier
Hepacivirus
Endothelial Cells
Virus Diseases
Brain
Virus Internalization
Central Nervous System
Virus Replication
Claudin-1
Nervous System Malformations
Virus Receptors
Scavenger Receptors
Polymerase Chain Reaction
Liver
Viral RNA
Interferons
Endothelium
Liver Diseases
Permeability
Peptide Hydrolases

Keywords

  • HCVcc
  • HCVpp
  • Neurologic Defect
  • Virus Tropism

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Fletcher, N. F., Wilson, G. K., Murray, J., Hu, K., Lewis, A., Reynolds, G. M., ... McKeating, J. A. (2012). Hepatitis C virus infects the endothelial cells of the blood-brain barrier. Gastroenterology, 142(3), 634-643. https://doi.org/10.1053/j.gastro.2011.11.028

Hepatitis C virus infects the endothelial cells of the blood-brain barrier. / Fletcher, Nicola F.; Wilson, Garrick K.; Murray, Jacinta; Hu, Ke; Lewis, Andrew; Reynolds, Gary M.; Stamataki, Zania; Meredith, Luke W.; Rowe, Ian A.; Luo, Guangxiang; Lopezramirez, Miguel A.; Baumert, Thomas F.; Weksler, Babette; Couraud, Pierreolivier; Kim, Kwang Sik; Romero, Ignacio A.; Jopling, Catherine; Morgello, Susan; Balfe, Peter; McKeating, Jane A.

In: Gastroenterology, Vol. 142, No. 3, 03.2012, p. 634-643.

Research output: Contribution to journalArticle

Fletcher, NF, Wilson, GK, Murray, J, Hu, K, Lewis, A, Reynolds, GM, Stamataki, Z, Meredith, LW, Rowe, IA, Luo, G, Lopezramirez, MA, Baumert, TF, Weksler, B, Couraud, P, Kim, KS, Romero, IA, Jopling, C, Morgello, S, Balfe, P & McKeating, JA 2012, 'Hepatitis C virus infects the endothelial cells of the blood-brain barrier', Gastroenterology, vol. 142, no. 3, pp. 634-643. https://doi.org/10.1053/j.gastro.2011.11.028
Fletcher NF, Wilson GK, Murray J, Hu K, Lewis A, Reynolds GM et al. Hepatitis C virus infects the endothelial cells of the blood-brain barrier. Gastroenterology. 2012 Mar;142(3):634-643. https://doi.org/10.1053/j.gastro.2011.11.028
Fletcher, Nicola F. ; Wilson, Garrick K. ; Murray, Jacinta ; Hu, Ke ; Lewis, Andrew ; Reynolds, Gary M. ; Stamataki, Zania ; Meredith, Luke W. ; Rowe, Ian A. ; Luo, Guangxiang ; Lopezramirez, Miguel A. ; Baumert, Thomas F. ; Weksler, Babette ; Couraud, Pierreolivier ; Kim, Kwang Sik ; Romero, Ignacio A. ; Jopling, Catherine ; Morgello, Susan ; Balfe, Peter ; McKeating, Jane A. / Hepatitis C virus infects the endothelial cells of the blood-brain barrier. In: Gastroenterology. 2012 ; Vol. 142, No. 3. pp. 634-643.
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AU - Fletcher, Nicola F.

AU - Wilson, Garrick K.

AU - Murray, Jacinta

AU - Hu, Ke

AU - Lewis, Andrew

AU - Reynolds, Gary M.

AU - Stamataki, Zania

AU - Meredith, Luke W.

AU - Rowe, Ian A.

AU - Luo, Guangxiang

AU - Lopezramirez, Miguel A.

AU - Baumert, Thomas F.

AU - Weksler, Babette

AU - Couraud, Pierreolivier

AU - Kim, Kwang Sik

AU - Romero, Ignacio A.

AU - Jopling, Catherine

AU - Morgello, Susan

AU - Balfe, Peter

AU - McKeating, Jane A.

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N2 - Background & Aims: Hepatitis C virus (HCV) infection leads to progressive liver disease and is associated with a variety of extrahepatic syndromes, including central nervous system (CNS) abnormalities. However, it is unclear whether such cognitive abnormalities are a function of systemic disease, impaired hepatic function, or virus infection of the CNS. Methods: We measured levels of HCV RNA and expression of the viral entry receptor in brain tissue samples from 10 infected individuals (and 3 uninfected individuals, as controls) and human brain microvascular endothelial cells by using quantitative polymerase chain reaction and immunochemical and confocal imaging analyses. HCV pseudoparticles and cell culturederived HCV were used to study the ability of endothelial cells to support viral entry and replication. Results: Using quantitative polymerase chain reaction, we detected HCV RNA in brain tissue of infected individuals at significantly lower levels than in liver samples. Brain microvascular endothelia and brain endothelial cells expressed all of the recognized HCV entry receptors. Two independently derived brain endothelial cell lines, hCMEC/D3 and HBMEC, supported HCV entry and replication. These processes were inhibited by antibodies against the entry factors CD81, scavenger receptor BI, and claudin-1; by interferon; and by reagents that inhibit NS3 protease and NS5B polymerase. HCV infection promotes endothelial permeability and cellular apoptosis. Conclusions: Human brain endothelial cells express functional receptors that support HCV entry and replication. Virus infection of the CNS might lead to HCV-associated neuropathologies.

AB - Background & Aims: Hepatitis C virus (HCV) infection leads to progressive liver disease and is associated with a variety of extrahepatic syndromes, including central nervous system (CNS) abnormalities. However, it is unclear whether such cognitive abnormalities are a function of systemic disease, impaired hepatic function, or virus infection of the CNS. Methods: We measured levels of HCV RNA and expression of the viral entry receptor in brain tissue samples from 10 infected individuals (and 3 uninfected individuals, as controls) and human brain microvascular endothelial cells by using quantitative polymerase chain reaction and immunochemical and confocal imaging analyses. HCV pseudoparticles and cell culturederived HCV were used to study the ability of endothelial cells to support viral entry and replication. Results: Using quantitative polymerase chain reaction, we detected HCV RNA in brain tissue of infected individuals at significantly lower levels than in liver samples. Brain microvascular endothelia and brain endothelial cells expressed all of the recognized HCV entry receptors. Two independently derived brain endothelial cell lines, hCMEC/D3 and HBMEC, supported HCV entry and replication. These processes were inhibited by antibodies against the entry factors CD81, scavenger receptor BI, and claudin-1; by interferon; and by reagents that inhibit NS3 protease and NS5B polymerase. HCV infection promotes endothelial permeability and cellular apoptosis. Conclusions: Human brain endothelial cells express functional receptors that support HCV entry and replication. Virus infection of the CNS might lead to HCV-associated neuropathologies.

KW - HCVcc

KW - HCVpp

KW - Neurologic Defect

KW - Virus Tropism

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