期刊
NATURE COMMUNICATIONS
卷 11, 期 1, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-020-15072-8
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资金
- German Research Council (DFG -Deutsche Forschungsgemeinschaft) [GRK2098, GRK2581, SFB974, GRK1949, GU 335/35-1, LA1419/71, LA1419/10-1, HU1824/7-1, SE1410/6-2, SFB1292/TP13]
- Fresenius Stiftung [2015_A232]
- EU 7th framework, MarieCurie Actions ITN-EDGE
- Programm zur internen Forschungsforderung Essen (IFORES) Research fellowship program of the University of Duisburg-Essen Medical School
- University of Duisburg-Essen
- GIF [I-1474-414,13/2918]
Macrophages have important protective functions during infection with herpes simplex virus type 1 (HSV-1). However, molecular mechanisms that restrict viral propagation and protect from severe disease are unclear. Here we show that macrophages take up HSV-1 via endocytosis and transport the virions into multivesicular bodies (MVBs). In MVBs, acid ceramidase (aCDase) converts ceramide into sphingosine and increases the formation of sphingosine-rich intraluminal vesicles (ILVs). Once HSV-1 particles reach MVBs, sphingosine-rich ILVs bind to HSV-1 particles, which restricts fusion with the limiting endosomal membrane and prevents cellular infection. Lack of aCDase in macrophage cultures or in Asah1(-/-) mice results in replication of HSV-1 and Asah1(-/-) mice die soon after systemic or intravaginal inoculation. The treatment of macrophages with sphingosine enhancing compounds blocks HSV-1 propagation, suggesting a therapeutic potential of this pathway. In conclusion, aCDase loads ILVs with sphingosine, which prevents HSV-1 capsids from penetrating into the cytosol.
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