Acid ceramidase of macrophages traps herpes simplex virus in multivesicular bodies and protects from severe disease

Author:

Lang JudithORCID,Bohn Patrick,Bhat Hilal,Jastrow Holger,Walkenfort Bernd,Cansiz Feyza,Fink Julian,Bauer MichaelORCID,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.,Hardt Cornelia,Probst Hans ChristianORCID,Schumacher FabianORCID,Köhrer KarlORCID,Kleuser Burkhard,Babiychuk Eduard B.,Sodeik BeateORCID,Seibel Jürgen,Greber Urs F.ORCID,Lang Philipp A.,Gulbins ErichORCID,Lang Karl S.

Abstract

AbstractMacrophages 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.

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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