Glycosphingolipid GM3 is Indispensable for Dengue Virus Genome Replication.
Dengue virus (DENV) causes the most prevalent arthropod-borne viral disease of humans worldwide. Glycosphingolipids (GSLs) are involved in virus infection by regulating various steps of viral-host interaction. However, the distinct role of GSLs during DENV infection remains unclear. In this study, we used mouse melanoma B16 cells and their GSL-deficient mutant counterpart GM95 cells to study the influence of GSLs on DENV infection. Surprisingly, GM95 cells were highly resistant to DENV infection compared with B16 cells. Pretreatment of B16 cells with synthetase inhibitor of GM3, the most abundant GSLs in B16 cells, or silencing GM3 synthetase T3GAL5, significantly inhibited DENV infection. DENV attachment and endocytosis were not impaired in GM95 cells, but DENV genome replication was obviously inhibited in GM95 cells compared to B16 cells. Furthermore, GM3 was colocalized with DENV viral replication complex on endoplasmic reticulum (ER) inside the B16 cells. Finally, GM3 synthetase inhibitor significantly reduced the mortality rate of suckling mice that challenged with DENV by impairing the viral replication in mouse brain. Taken together, these data indicated that GM3 was not required for DENV attachment and endocytosis, however, essential for viral genome replication. Targeting GM3 could be a novel strategy to inhibit DENV infection.
1. Institutes of Biology and Medical Sciences, Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou 215123, P.R. China.
Kezhen
K
Wang
1. Institutes of Biology and Medical Sciences, Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou 215123, P.R. China.
Juanjuan
J
Wang
1. Institutes of Biology and Medical Sciences, Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou 215123, P.R. China.
Ta
T
Sun
1. Institutes of Biology and Medical Sciences, Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou 215123, P.R. China.
Gang
G
Bian
1. Institutes of Biology and Medical Sciences, Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou 215123, P.R. China.
Wen
W
Pan
1. Institutes of Biology and Medical Sciences, Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou 215123, P.R. China.
Tingting
T
Feng
2. Department of Microbiology and Immunology, New York Medical College, Valhalla, NY 10595, USA.
Penghua
P
Wang
1. Institutes of Biology and Medical Sciences, Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou 215123, P.R. China.
Yunsen
Y
Li
1. Institutes of Biology and Medical Sciences, Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou 215123, P.R. China.
Jianfeng
J
Dai
D000818:Animals; D045744:Cell Line, Tumor; D003716:Dengue Virus / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D005416:Flavivirus / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D016679:Genome, Viral / Q000235:genetics*; D006017:Glycolipids / Q000378:metabolism; D006028:Glycosphingolipids / Q000378:metabolism*; D051379:Mice; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000235:genetics / Q000502:physiology*
D006017:Glycolipids; D006028:Glycosphingolipids; D017361:Viral Nonstructural Proteins
Dengue Virus; Flavivirus; Glycolipid; Glycosphingolipids; Lipid Synthesis; Viral Replication