Host sphingomyelin increases West Nile virus infection in vivo

Flaviviruses, such as the dengue virus and the West Nile virus (WNV), are arthropod-borne viruses that represent a global health problem. The flavivirus lifecycle is intimately connected to cellular lipids. Among the lipids co-opted by flaviviruses, we have focused on SM, an important component of c...

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Bibliographic Details
Published in:Journal of lipid research 2016-03, Vol.57 (3), p.422-432
Main Authors: Martín-Acebes, Miguel A., Gabandé-Rodríguez, Enrique, García-Cabrero, Ana M., Sánchez, Marina P., Ledesma, María Dolores, Sobrino, Francisco, Saiz, Juan-Carlos
Format: Article
Language:English
Subjects:
Animals
Brain - metabolism
Brain - virology
brain lipids
Endoplasmic Reticulum - metabolism
Endoplasmic Reticulum - virology
Female
Fibroblasts - metabolism
Fibroblasts - virology
flavivirus
Gene Knockout Techniques
Host-Pathogen Interactions
Humans
Intracellular Membranes - metabolism
Intracellular Membranes - virology
lipids
Male
Mice
Mice, Inbred C57BL
Niemann-Pick disease
Niemann-Pick Diseases - pathology
sphingolipids
Sphingomyelin Phosphodiesterase - deficiency
Sphingomyelin Phosphodiesterase - genetics
Sphingomyelins - metabolism
storage diseases
Virus Replication
West Nile virus - physiology
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Summary:Flaviviruses, such as the dengue virus and the West Nile virus (WNV), are arthropod-borne viruses that represent a global health problem. The flavivirus lifecycle is intimately connected to cellular lipids. Among the lipids co-opted by flaviviruses, we have focused on SM, an important component of cellular membranes particularly enriched in the nervous system. After infection with the neurotropic WNV, mice deficient in acid sphingomyelinase (ASM), which accumulate high levels of SM in their tissues, displayed exacerbated infection. In addition, WNV multiplication was enhanced in cells from human patients with Niemann-Pick type A, a disease caused by a deficiency of ASM activity resulting in SM accumulation. Furthermore, the addition of SM to cultured cells also increased WNV infection, whereas treatment with pharmacological inhibitors of SM synthesis reduced WNV infection. Confocal microscopy analyses confirmed the association of SM with viral replication sites within infected cells. Our results unveil that SM metabolism regulates flavivirus infection in vivo and propose SM as a suitable target for antiviral design against WNV.
ISSN:0022-2275
1539-7262
DOI:10.1194/jlr.M064212