Direct complement restriction of flavivirus infection requires glycan recognition by mannose-binding lectin.
An intact complement system is crucial for limiting West Nile virus (WNV) dissemination. Herein, we define how complement directly restricts flavivirus infection in an antibody-independent fashion. Mannose-binding lectin (MBL) recognized N-linked glycans on the structural proteins of WNV and Dengue virus (DENV), resulting in neutralization through a C3- and C4-dependent mechanism that utilized both the canonical and bypass lectin activation pathways. For WNV, neutralization occurred with virus produced in insect cells, whereas for DENV, neutralization of insect and mammalian cell-derived virus was observed. Mechanism of action studies suggested that the MBL-dependent neutralization occurred, in part, by blocking viral fusion. Experiments in mice showed an MBL-dependent accelerated intravascular clearance of DENV or a WNV mutant with two N-linked glycans on its E protein, but not with wild-type WNV. Our studies show that MBL recognizes terminal mannose-containing carbohydrates on flaviviruses, resulting in neutralization and efficient clearance in vivo.
Fuchs
Anja
A
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Lin
Tsai-Yu
TY
Beasley
David W
DW
Stover
Cordula M
CM
Schwaeble
Wilhelm J
WJ
Pierson
Theodore C
TC
Diamond
Michael S
MS
D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D002460:Cell Line; D003176:Complement C3 / Q000276:immunology*; D003181:Complement C4 / Q000276:immunology*; D003715:Dengue / Q000276:immunology* / Q000821:virology; D003716:Dengue Virus / Q000276:immunology* / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D037601:Mannose-Binding Lectin / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011134:Polysaccharides / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000378:metabolism; D014901:West Nile Fever / Q000276:immunology* / Q000821:virology; D014902:West Nile virus / Q000378:metabolism / Q000502:physiology*
D057134:Antibodies, Neutralizing; D003176:Complement C3; D003181:Complement C4; D037601:Mannose-Binding Lectin; D011134:Polysaccharides; D014759:Viral Envelope Proteins