Journal Article

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

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

2020

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/31 / 14/19 / 14/28 / 38/61 / 631/250 / 631/250/254 / 631/45/287/1196 / 631/80/313/1727 / 631/80/313/2378 / 64/110 / 64/60 / 82/58 / 82/80 / Acid Ceramidase - genetics / Acid Ceramidase - metabolism / Animals / Antiviral agents / Antiviral drugs / Capsids / Ceramidase / Ceramide / Constraining / Cytosol / Endocytosis / Female / Herpes simplex / Herpes Simplex - enzymology / Herpes Simplex - prevention & control / Herpes Simplex - virology / Herpes viruses / Herpesvirus 1, Human - physiology / Humanities and Social Sciences / Humans / Inoculation / Macrophages / Macrophages - enzymology / Macrophages - virology / Mice / Mice, Inbred C57BL / Mice, Knockout / Molecular modelling / multidisciplinary / Multivesicular Bodies - virology / Propagation / Replication / Science / Science (multidisciplinary) / Virions / Virus Replication / Viruses