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

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.; Hardt, Cornelia; Probst, Hans Christian; Schumacher, Fabian; Köhrer, Karl; Kleuser, Burkhard; Babiychuk, Eduard B.; Sodeik, Beate; Seibel, Jürgen; Greber, Urs F.; Lang, Philipp A.; Gulbins, Erich; Lang, Karl S.

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.