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

2020; Nature Portfolio; Volume: 11; Issue: 1 Linguagem: Inglês

10.1038/s41467-020-15072-8

2041-1723

Judith Lang, Patrick Bohn, Hilal Bhat, Holger Jastrow, Bernd Walkenfort, Feyza Cansiz, Julian Fink, Michael Bauer, Dominik Olszewski, Ana Ramos-Nascimento, Vikas Duhan, Sarah-Kim Friedrich, Katrin Anne Becker, Adalbert Krawczyk, Michael J. Edwards, Andreas Burchert, Magdalena Huber, Justa Friebus‐Kardash, Joachim R. Göthert, Cornelia Hardt, Hans Christian Probst, Fabian Schumacher, Karl Köhrer, Burkhard Kleuser, Eduard B. Babiychuk, Beate Sodeik, Jürgen Seibel, Urs F. Greber, Philipp A. Lang, Erich Gulbins, Karl S. Lang,

Research on Leishmaniasis Studies

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.