TY  - JOUR
A1  - Avota, Elita
A1  - Bodem, Jochen
A1  - Chithelen, Janice
A1  - Mandasari, Putri
A1  - Beyersdorf, Niklas
A1  - Schneider-Schaulies, Jürgen
T1  - The Manifold Roles of Sphingolipids in Viral Infections
JF  - Frontiers in Physiology
N2  - Sphingolipids are essential components of eukaryotic cells. In this review, we want to exemplarily illustrate what is known about the interactions of sphingolipids with various viruses at different steps of their replication cycles. This includes structural interactions during entry at the plasma membrane or endosomal membranes, early interactions leading to sphingolipid-mediated signal transduction, interactions with internal membranes and lipids during replication, and interactions during virus assembly and budding. Targeted interventions in sphingolipid metabolism – as far as they can be tolerated by cells and organisms – may open novel possibilities to support antiviral therapies. Human immunodeficiency virus type 1 (HIV-1) infections have intensively been studied, but for other viral infections, such as influenza A virus (IAV), measles virus (MV), hepatitis C virus (HCV), dengue virus, Ebola virus, and severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), investigations are still in their beginnings. As many inhibitors of sphingolipid metabolism are already in clinical use against other diseases, repurposing studies for applications in some viral infections appear to be a promising approach.
KW  - sphingolipid
KW  - ceramide
KW  - sphingosine-1-phosphate
KW  - plasma membrane
KW  - virus entry
KW  - virus replication
KW  - virus budding
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246975
SN  - 1664-042X
VL  - 12
ER  - 
TY  - JOUR
A1  - Geiger, Nina
A1  - Kersting, Louise
A1  - Schlegel, Jan
A1  - Stelz, Linda
A1  - Fähr, Sofie
A1  - Diesendorf, Viktoria
A1  - Roll, Valeria
A1  - Sostmann, Marie
A1  - König, Eva-Maria
A1  - Reinhard, Sebastian
A1  - Brenner, Daniela
A1  - Schneider-Schaulies, Sibylle
A1  - Sauer, Markus
A1  - Seibel, Jürgen
A1  - Bodem, Jochen
T1  - The acid ceramidase is a SARS-CoV-2 host factor
JF  - Cells
N2  - SARS-CoV-2 variants such as the delta or omicron variants, with higher transmission rates, accelerated the global COVID-19 pandemic. Thus, novel therapeutic strategies need to be deployed. The inhibition of acid sphingomyelinase (ASM), interfering with viral entry by fluoxetine was reported. Here, we described the acid ceramidase as an additional target of fluoxetine. To discover these effects, we synthesized an ASM-independent fluoxetine derivative, AKS466. High-resolution SARS-CoV-2–RNA FISH and RTqPCR analyses demonstrate that AKS466 down-regulates viral gene expression. It is shown that SARS-CoV-2 deacidifies the lysosomal pH using the ORF3 protein. However, treatment with AKS488 or fluoxetine lowers the lysosomal pH. Our biochemical results show that AKS466 localizes to the endo-lysosomal replication compartments of infected cells, and demonstrate the enrichment of the viral genomic, minus-stranded RNA and mRNAs there. Both fluoxetine and AKS466 inhibit the acid ceramidase activity, cause endo-lysosomal ceramide elevation, and interfere with viral replication. Furthermore, Ceranib-2, a specific acid ceramidase inhibitor, reduces SARS-CoV-2 replication and, most importantly, the exogenous supplementation of C6-ceramide interferes with viral replication. These results support the hypotheses that the acid ceramidase is a SARS-CoV-2 host factor.
KW  - SARS-CoV-2
KW  - ceramides
KW  - ceramidase
KW  - fluoxetine
KW  - acid sphingomyelinase
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286105
SN  - 2073-4409
VL  - 11
IS  - 16
ER  - 
TY  - JOUR
A1  - Brenner, Daniela
A1  - Geiger, Nina
A1  - Schlegel, Jan
A1  - Diesendorf, Viktoria
A1  - Kersting, Louise
A1  - Fink, Julian
A1  - Stelz, Linda
A1  - Schneider-Schaulies, Sibylle
A1  - Sauer, Markus
A1  - Bodem, Jochen
A1  - Seibel, Jürgen
T1  - Azido-ceramides, a tool to analyse SARS-CoV-2 replication and inhibition — SARS-CoV-2 is inhibited by ceramides
JF  - International Journal of Molecular Sciences
N2  - Recently, we have shown that C6-ceramides efficiently suppress viral replication by trapping the virus in lysosomes. Here, we use antiviral assays to evaluate a synthetic ceramide derivative α-NH2-ω-N3-C6-ceramide (AKS461) and to confirm the biological activity of C6-ceramides inhibiting SARS-CoV-2. Click-labeling with a fluorophore demonstrated that AKS461 accumulates in lysosomes. Previously, it has been shown that suppression of SARS-CoV-2 replication can be cell-type specific. Thus, AKS461 inhibited SARS-CoV-2 replication in Huh-7, Vero, and Calu-3 cells up to 2.5 orders of magnitude. The results were confirmed by CoronaFISH, indicating that AKS461 acts comparable to the unmodified C6-ceramide. Thus, AKS461 serves as a tool to study ceramide-associated cellular and viral pathways, such as SARS-CoV-2 infections, and it helped to identify lysosomes as the central organelle of C6-ceramides to inhibit viral replication.
KW  - ceramides
KW  - SARS-CoV-2
KW  - azido-ceramides
KW  - sphingolipids
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-313581
SN  - 1422-0067
VL  - 24
IS  - 8
ER  -