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.

Not all of our DENV neutralization studies with human serum containing different levels of MBL were readily explained. Whereas reconstitution of serum from donor 2 with purified MBL restored neutralization of insect cell-derived DENV-2, addition of even higher concentrations of purified MBL to serum from donor 2 failed to inhibit mammalian cell-derived DENV-2, yet complementation with low concentrations of serum from donor 1 did. Although additional studies are warranted, purified human MBL may interact with downstream complement proteins (e.g., MASP-2) in the serum from donor 2, albeit with lower affinity compared to the native MBL from donor 1. As another example, we also observed differential neutralizing capacity of sera from individuals (donors 3, 7, and 12 or donors 6, 10, and 13) with similar plasma MBL levels and no difference in C4 levels and CH50 activity. In contrast to wild-type MBL, which comprises a mixture of higher-order 200-to 700-kDa oligomers, some MBL point mutation variants preferentially form low-molecular-mass (120-to 130-kDa) complexes in circulation; these complexes do not bind well to mannan and activate the lectin pathway less efficiently (15) . Variability in the oligomeric state of circulating MBL among individuals independently could contribute to differences in relative neutralization in the setting of similar MBL levels. Ficolin is another pattern recognition molecule of the lectin pathway whose blood levels vary among individuals due to genetic polymorphisms (51) . As serum MASPs also associate with ficolins (10), variation in ficolin levels could differentially sequester MASPs and explain some of the discordant results.