title: Inhibition of c3 convertase activity by hepatitis C virus as an additional lesion in the regulation of complement components.
abstract: We have previously reported that in vitro HCV infection of cells of hepatocyte origin attenuates complement system at multiple steps, and attenuation also occurs in chronically HCV infected liver, irrespective of the disease stage. However, none of these regulations alone completely impaired complement pathways. Modulation of the upstream proteins involved in proteolytic processing of the complement cascade prior to convertase formation is critical in promoting the function of the complement system in response to infection. Here, we examined the regulation of C2 complement expression in hepatoma cells infected in vitro with cell culture grown virus, and validated our observations using randomly selected chronically HCV infected patient liver biopsy specimens. C2 mRNA expression was significantly inhibited, and classical C3 convertase (C4b2a) decreased. In separate experiments for C3 convertase function, C3b deposition onto bacterial membrane was reduced using HCV infected patient sera as compared to uninfected control, suggesting impaired C3 convertase. Further, iC3b level, a proteolytically inactive form of C3b, was lower in HCV infected patient sera, reflecting impairment of both C3 convertase and Factor I activity. The expression level of Factor I was significantly reduced in HCV infected liver biopsy specimens, while Factor H level remained unchanged or enhanced. Together, these results suggested that inhibition of C3 convertase activity is an additional cumulative effect for attenuation of complement system adopted by HCV for weakening innate immune response.
authors.affiliation: Department of Internal Medicine, Saint Louis University, St. Louis, Missouri, United States of America.
authors.forename: Hangeun
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Saint Louis University, St. Louis, Missouri, United States of America.
authors.forename: Keith
authors.initials: K
authors.lastname: Meyer
authors.affiliation: Department of Internal Medicine, Saint Louis University, St. Louis, Missouri, United States of America; Department of Molecular Microbiology & Immunology, Saint Louis University, St. Louis, Missouri, United States of America.
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Di Bisceglie
authors.affiliation: Department of Internal Medicine, Saint Louis University, St. Louis, Missouri, United States of America; Department of Molecular Microbiology & Immunology, Saint Louis University, St. Louis, Missouri, United States of America.
authors.forename: Ranjit
authors.initials: R
authors.lastname: Ray
mesh_terms: D003175:Complement C2 / Q000096:biosynthesis*; D050577:Complement C3-C5 Convertases / Q000378:metabolism*; D003179:Complement C3b / Q000096:biosynthesis*; D017242:Complement Factor H / Q000096:biosynthesis*; D005260:Female; D005786:Gene Expression Regulation; D016174:Hepacivirus; D019698:Hepatitis C, Chronic / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007113:Immunity, Innate; D008099:Liver / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D008297:Male; D012333:RNA, Messenger / Q000096:biosynthesis
chemical_list: D003175:Complement C2; D012333:RNA, Messenger; D003179:Complement C3b; D017242:Complement Factor H; D050577:Complement C3-C5 Convertases