1. Acid ceramidase of macrophages traps herpes simplex virus in multivesicular bodies and protects from severe disease.
- Author
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Lang, Judith, Bohn, Patrick, Bhat, Hilal, Jastrow, Holger, Walkenfort, Bernd, Cansiz, Feyza, Fink, Julian, Bauer, Michael, Olszewski, Dominik, Ramos-Nascimento, Ana, Duhan, Vikas, Friedrich, Sarah-Kim, Becker, Katrin Anne, Krawczyk, Adalbert, Edwards, Michael J., Burchert, Andreas, Huber, Magdalena, Friebus-Kardash, Justa, Göthert, Joachim R., and Hardt, Cornelia
- Subjects
HERPES simplex virus ,HUMAN herpesvirus 1 ,ENDOCYTOSIS - Abstract
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. Macrophages are critical in limiting replication of herpes simplex virus type 1 (HSV-1). Here the authors show how acid ceramidase and its enzymatic product sphingosine enable multivesicular bodies to function as an anti-viral mechanism. [ABSTRACT FROM AUTHOR]- Published
- 2020
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