Complement-Mediated Neutralization of Dengue Virus Requires Mannose-Binding Lectin

Avirutnan, Panisadee; Hauhart, Richard E.; Marovich, Mary A.; Garred, Peter; Atkinson, John P.; Diamond, Michael S.

MBL is a calcium-dependent (C-type) lectin that recognizes adjacent equatorial monosaccharide hydroxyl groups that are present on mannose, N-acetylglucosamine (GlcNAc), and fucose and displayed on a range of microorganisms (14) . Human MBL is encoded by the MBL2 gene, and polymorphisms result in highly variable MBL activity in human plasma (15) . Three singlenucleotide polymorphisms (SNPs) (alleles B [codon 54], C [codon 57], and D [codon 52]) are located in exon 1 and affect the structural and functional integrity of the protein (15) . Additional SNPs in the promoter (H/L variants at position Ϫ550 and X/Y variants at position Ϫ221) and 5= untranslated (P/Q variants at position ϩ4) regions of the MBL2 gene influence the basal level of MBL in serum (15) . Low MBL serum levels and variant MBL alleles have been associated with enhanced susceptibility to infection in young children and immunocompromised patients (reviewed in references 16 and 17) . In adults, low serum MBL concentrations have been suggested to influence disease progression associated with HIV, hepatitis B, hepatitis C, and herpes simplex virus infections (18) (19) (20) (21) . Although the complement system has been suggested to play a role in DENV pathogenesis, in particular, during the secondary infection (22) (23) (24) , its roles in protection against DENV remain uncertain. Here, we show that human MBL bound to insect celland mammalian cell-derived DENV and neutralized infection of all DENV serotypes through complement activation-dependent and -independent pathways. Moreover, we observed a direct correlation with the concentration of MBL in human serum and neutralization of DENV. Our studies suggest that allelic variation of MBL in humans may impact complement-dependent control of DENV infection.