title: Host sphingomyelin increases West Nile virus infection in vivo.
abstract: 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.
authors.affiliation: Departments of Virology and Microbiology Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Madrid 28049, Spain Department of Biotechnology, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA), Madrid 28040, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Martín-Acebes
authors.affiliation: Molecular Neurobiology, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Madrid 28049, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Gabandé-Rodríguez
authors.affiliation: Laboratory of Neurology, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid 28040, Spain.
authors.forename: Ana M
authors.initials: AM
authors.lastname: García-Cabrero
authors.affiliation: Laboratory of Neurology, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid 28040, Spain.
authors.forename: Marina P
authors.initials: MP
authors.lastname: Sánchez
authors.affiliation: Molecular Neurobiology, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Madrid 28049, Spain.
authors.forename: María Dolores
authors.initials: MD
authors.lastname: Ledesma
authors.affiliation: Departments of Virology and Microbiology Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Madrid 28049, Spain fsobrino@cbm.csic.es jcsaiz@inia.es.
authors.forename: Francisco
authors.initials: F
authors.lastname: Sobrino
authors.affiliation: Department of Biotechnology, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA), Madrid 28040, Spain fsobrino@cbm.csic.es jcsaiz@inia.es.
authors.forename: Juan-Carlos
authors.initials: JC
authors.lastname: Saiz
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000821:virology; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000821:virology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000821:virology; D055786:Gene Knockout Techniques; D054884:Host-Pathogen Interactions; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009542:Niemann-Pick Diseases / Q000473:pathology; D013108:Sphingomyelin Phosphodiesterase / Q000172:deficiency / Q000235:genetics; D013109:Sphingomyelins / Q000378:metabolism*; D014779:Virus Replication; D014902:West Nile virus / Q000502:physiology*
chemical_list: D013109:Sphingomyelins; D013108:Sphingomyelin Phosphodiesterase
keywords: Niemann-Pick disease; brain lipids; flavivirus; lipids; sphingolipids; storage diseases