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

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

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.

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Lang, J., Bohn, P., Bhat, H., Jastrow, H., Walkenfort, B., Cansiz, F., Fink, J., Bauer, M., Olszewski, D., Ramos-Nascimento, A., Duhan, V., Friedrich, S.-K., Becker, K.A., Krawczyk, A., Edwards, M.J., Burchert, A., Huber, M., Friebus-Kardash, J., Göthert, J.R., Hardt, C., Probst, H.C., Schumacher, F., Köhrer, K., Kleuser, B., Babiychuk, E.B., Sodeik, B., Seibel, J., Greber, U.F., Lang, P.A., Gulbins, E., Lang, K.S., 2020. Acid ceramidase of macrophages traps herpes simplex virus in multivesicular bodies and protects from severe disease. https://doi.org/10.1038/s41467-020-15072-8
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