TY - JOUR
T1 - Direct complement restriction of flavivirus infection requires glycan recognition by mannose-binding lectin
AU - Fuchs, Anja
AU - Lin, Tsai Yu
AU - Beasley, David W.
AU - Stover, Cordula M.
AU - Schwaeble, Wilhelm J.
AU - Pierson, Theodore C.
AU - Diamond, Michael S.
N1 - Funding Information:
We thank J. Atkinson for critical comments on the manuscript. We also thank X. Wu for the C3 −/− × C4 −/− mice and C. Tedford (Omeros, Inc) for shipment of the MASP-2 −/− mice. This work was supported by the Intramural Research Program of the National Institutes of Allergy and Infectious Diseases (NIAID) and grants from the National Institutes of Health (NIH) (R01 AI073755 and the Midwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research [U54 AI057160]).
PY - 2010/8/19
Y1 - 2010/8/19
N2 - 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.
AB - 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.
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U2 - 10.1016/j.chom.2010.07.007
DO - 10.1016/j.chom.2010.07.007
M3 - Article
C2 - 20709295
AN - SCOPUS:77956333920
SN - 1931-3128
VL - 8
SP - 186
EP - 195
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 2
ER -