Abstract
Human ficolin-2 (L-ficolin/p35) is a lectin-complement pathway activator that is present in normal human plasma and is associated with infectious diseases; however, little is known regarding the roles and mechanisms of ficolin-2 during chronic hepatitis C virus (HCV) infection. In this study, we found that ficolin-2 inhibits the entry of HCV at an early stage of viral infection, regardless of the viral genotype. Ficolin-2 neutralized and inhibited the initial attachment and infection of HCV by binding to the HCV envelope surface glycoproteins E1 and E2, blocking HCV attachment to low-density lipoprotein receptor (LDLR) and scavenger receptor B1, and weakly interfering with CD81 receptor attachment. However, no interference with claudin-1 and occludin receptor attachment was observed. The C-terminal fibrinogen domain (201-313 aa) of ficolin-2 was identified as the critical binding region for the HCV-E1-E2 N-glycans, playing a critical role in the anti-HCV activity. More importantly, we found that apolipoprotein E (ApoE)3, which is enriched in the low-density fractions of HCV RNA-containing particles, promotes HCV infection and inhibits ficolin-2-mediated antiviral activity. ApoE3, but not ApoE2 and ApoE4, blocked the interaction between ficolin-2 and HCV-E2. Our data suggest that the HCV entry inhibitor ficolin-2 is a novel and promising antiviral innate immune molecule, whereas ApoE3 blocks the effect of ficolin-2 and mediates an immune escape mechanism during chronic HCV infection. HCV may be neutralized using compounds directed against the lipoprotein moiety of the viral particle, and ApoE3 may be a new target to combat HCV infection.
Highlights
Why The JI? Submit online. Rapid Reviews! 30 days* from submission to initial decision No Triage! Every submission reviewed by practicing scientists Fast Publication! 4 weeks from acceptance to publicatio
Western blotting analysis showed that hepatitis C virus (HCV)-NS3 expression was decreased in the presence of ficolin-2, which indicated that ficolin-2 blocked and neutralized HCV cell culture (HCVcc) infection (Fig. 1B)
We have demonstrated that this human lectin inhibited the entry of HCVcc and all six genotypes of HCV pseudotyped particles (HCVpp) at the early stages of virus entry, regardless of the genotype
Summary
For neutralization of HCV infectivity, HCV was incubated with different amounts of GST–ficolin-2 or GST protein at 37 ̊C or mixed with ApoE3 (0.15 mM) for 1 h and added to Huh7.5.1 cells. HCV-NS3 protein expression was detected by Western blot using an anti-NS3 mAb. To determine the effects of mannan and GlcNAc on ficolin-2’s inhibition of HCV infection, ficolin-2 (0.1 mM) was incubated with different concentrations of mannan and GlcNAc for 1 h.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
