title: Ficolin-2 inhibits hepatitis C virus infection, whereas apolipoprotein E3 mediates viral immune escape.
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.
authors.affiliation: State Key Laboratory of Virology, Department of Immunology, Hubei Province Key Laboratory of Allergy and Immunology, Wuhan University School of Medicine, Wuhan 430071, China;
authors.forename: Yinglan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Virology, Department of Immunology, Hubei Province Key Laboratory of Allergy and Immunology, Wuhan University School of Medicine, Wuhan 430071, China;
authors.forename: Yushan
authors.initials: Y
authors.lastname: Ren
authors.affiliation: State Key Laboratory of Virology, Department of Immunology, Hubei Province Key Laboratory of Allergy and Immunology, Wuhan University School of Medicine, Wuhan 430071, China;
authors.forename: Xuping
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Microbiology, Second Military Medical University, Shanghai 200433, China;
authors.forename: Ping
authors.initials: P
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Shanghai 200025, China; and.
authors.forename: Wanyin
authors.initials: W
authors.lastname: Tao
authors.affiliation: Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Shanghai 200025, China; and.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhong
authors.affiliation: University of Michigan Medical Center, Ann Arbor, MI 48109.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Li
authors.affiliation: State Key Laboratory of Virology, Department of Immunology, Hubei Province Key Laboratory of Allergy and Immunology, Wuhan University School of Medicine, Wuhan 430071, China; zhangxiaolian@whu.edu.cn.
authors.forename: Xiao-Lian
authors.initials: XL
authors.lastname: Zhang
mesh_terms: D053318:Apolipoprotein E3 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001667:Binding, Competitive / Q000276:immunology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D037102:Lectins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008351:Mannans / Q000276:immunology / Q000378:metabolism; D018613:Microscopy, Confocal; D011134:Polysaccharides / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D034622:RNA Interference; D011973:Receptors, LDL / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D060225:Tetraspanin 28 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019139:Tumor Escape / Q000235:genetics / Q000276:immunology*; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000097604:Ficolins
chemical_list: D053318:Apolipoprotein E3; D049452:Green Fluorescent Proteins; D037102:Lectins; D008351:Mannans; D011134:Polysaccharides; D011973:Receptors, LDL; D051122:Scavenger Receptors, Class B; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins; D000097604:Ficolins; C554798:CD81 protein, human; C087035:E1 protein, Hepatitis C virus; C495124:SCARB1 protein, human; C091015:glycoprotein E2, Hepatitis C virus