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.
Highlights
A significant number of people infected with HCV develop chronic infection [1,2]
The results clearly indicated that HCV infection regulates component 2 (C2) complement component at the transcriptional level at different magnitude based on HCV genotype
In order to investigate the effect of HCV infection on C2 expression in chronically infected patients, C2 mRNA status was measured from liver biopsy samples
Summary
A significant number of people infected with HCV develop chronic infection [1,2]. Hepatocytes are the primary host for HCV replication and serve as a main source for complement synthesis. All three complement activation pathways (classical, lectin, and alternative), merge for the cleavage of C3 in to C3a and C3b by C3 convertase. Cleavage of C3 by C3 convertases results in the formation of C3b and the anaphylatoxin C3a. Further processing of C3b results in the formation of iC3b and C3f, and C3c and C3dg [6]. In this process, Factor I is a key serine protease that inactivates all complement pathways by degrading activated complement factors C4b and C3b. Deficiencies in complement predispose patients to infection via ineffective opsonization, and defects in membrane attack complex (MAC) mediated lysis activity [8,9]. Insights into the mechanisms of complement regulation are crucial for understanding disease pathology and therapies
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