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

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 and Karl S. Lang ()
Additional contact information
Judith Lang: University of Duisburg-Essen
Patrick Bohn: University of Duisburg-Essen
Hilal Bhat: University of Duisburg-Essen
Holger Jastrow: University of Duisburg-Essen
Bernd Walkenfort: University of Duisburg-Essen
Feyza Cansiz: University of Duisburg-Essen
Julian Fink: Julius-Maximilians University of Würzburg
Michael Bauer: University of Zurich
Dominik Olszewski: University of Zurich
Ana Ramos-Nascimento: Hannover Medical School
Vikas Duhan: University of Duisburg-Essen
Sarah-Kim Friedrich: University of Duisburg-Essen
Katrin Anne Becker: University of Duisburg-Essen
Adalbert Krawczyk: University of Duisburg-Essen
Michael J. Edwards: University of Cincinnati
Andreas Burchert: University Hospital Giessen and Marburg, Campus Marburg
Magdalena Huber: Philipps-University Marburg
Justa Friebus-Kardash: University of Duisburg-Essen
Joachim R. Göthert: University Hospital of Essen, University of Duisburg-Essen
Cornelia Hardt: University of Duisburg-Essen
Hans Christian Probst: University Medical Center Mainz
Fabian Schumacher: University of Duisburg-Essen
Karl Köhrer: Heinrich-Heine−University, Universitätsstr. 1
Burkhard Kleuser: University of Potsdam
Eduard B. Babiychuk: University of Bern
Beate Sodeik: Hannover Medical School
Jürgen Seibel: Julius-Maximilians University of Würzburg
Urs F. Greber: University of Zurich
Philipp A. Lang: Heinrich Heine University, Universitätsstr. 1
Erich Gulbins: University of Duisburg-Essen
Karl S. Lang: University of Duisburg-Essen

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15072-8

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