Differential utilisation of ceramide during replication of the flaviviruses West Nile and dengue virus

Aktepe, Turgut E.; Pham, Helen; Mackenzie, Jason M.

doi:10.1016/j.virol.2015.06.015

Cited by 57 publications

(65 citation statements)

References 45 publications

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“…Treatment with TOFA reduced the synthesis of multiple cellular lipids, including those previously described to be involved in WNV infection, such as GPLs, SLs, and CHOL (8,10,15). Our electron microscopy results showed that TOFA induced a reduction in the amount of membrane rearrangements associated with WNV replication.…”

Section: Discussionsupporting

confidence: 59%

“…The replication of the viral genomic RNA and flavivirus nascent virion assembly take place in modified membranes from the endoplasmic reticulum (4)(5)(6)(7). To build an adequate microenvironment to support viral replication and particle biogenesis, flaviviruses rearrange host cell lipid metabolism by promoting the synthesis and accumulation of specific cellular lipids (i.e., fatty acids, glycerophospholipids [GPLs], sphingolipids [SLs], and cholesterol) (8)(9)(10)(11)(12)(13)(14)(15). This makes the pharmacological manipulation of cellular lipids an attractive antiviral strategy against WNV and related flaviviruses (13,14,16,17).…”

mentioning

confidence: 99%

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Modification of the Host Cell Lipid Metabolism Induced by Hypolipidemic Drugs Targeting the Acetyl Coenzyme A Carboxylase Impairs West Nile Virus Replication

Merino-Ramos

Vázquez-Calvo

Casas

et al. 2016

Antimicrob Agents Chemother

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West Nile virus (WNV) is a mosquito-borne neurotropic flavivirus responsible for recurrent outbreaks of meningitis and encephalitis affecting humans, horses, and birds in Africa, Europe, Asia, Oceania, and America (1). A great effort has been devoted in the past several years to decipher the molecular biology of WNV and its interaction with the host immune system (2, 3). Nevertheless, no licensed vaccine or therapy for human use against this pathogen is yet available.The flavivirus life cycle (including that of WNV) is intimately associated with host cell lipids. The replication of the viral genomic RNA and flavivirus nascent virion assembly take place in modified membranes from the endoplasmic reticulum (4-7). To build an adequate microenvironment to support viral replication and particle biogenesis, flaviviruses rearrange host cell lipid metabolism by promoting the synthesis and accumulation of specific cellular lipids (i.e., fatty acids, glycerophospholipids [GPLs], sphingolipids [SLs], and cholesterol) (8-15). This makes the pharmacological manipulation of cellular lipids an attractive antiviral strategy against WNV and related flaviviruses (13,14,16,17).The first steps of lipid biogenesis involve the synthesis and elongation of fatty acids, which provide the building blocks for the synthesis of more-complex lipids. Hence, fatty acid synthesis and elongation have become key targets for antiviral therapy (13,18,19). Regarding the flaviviruses, the pharmacological blockage of the fatty acid synthase FASN (which catalyzes the synthesis of palmitate from acetyl coenzyme A [acetyl-CoA] and malonylCoA into long-chain saturated fatty acids) reduced the viral replication (11, 13). The enzyme preceding FASN in the fatty acid biosynthetic route is the acetyl-CoA carboxylase (ACC), which catalyzes the carboxylation of acetyl-CoA to malonyl-CoA. Due to its rate-limiting role in fatty acid synthesis, ACC is currently a target of increasing interest within the pharmacological industry (20, 21). However, to our knowledge, the involvement of ACC in the replication of WNV, or other related flaviviruses, has not yet been evaluated.In this work, we have shown that ACC inhibitors alter the cellular lipid composition and reduce the levels of WNV infection in cultured cells. Furthermore, infection by Usutu virus (USUV; a related emerging flavivirus [22]) was also inhibited by the drugs used. Our results point to ACC as a potential druggable antiviral target against WNV and related flaviviruses. MATERIALS AND METHODSCells, viruses, infections, and virus titrations. All infectious virus manipulations were performed in biosafety level 3 (BSL-3) facilities. Vero, HeLa, and Neuro2a (N2a) cell lines were cultured as described previously (10, 23). Cells were incubated with the corresponding virus, WNV strain NY99 or USUV strain SAAR-1776 (24), for 1 h at 37°C; viral inoculum was removed; and infected cells were incubated in culture medium containing 1% fetal bovine serum (time that was considered 1 h postinfection [p.i.]).

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Section: Discussionsupporting

confidence: 59%

mentioning

confidence: 99%

Modification of the Host Cell Lipid Metabolism Induced by Hypolipidemic Drugs Targeting the Acetyl Coenzyme A Carboxylase Impairs West Nile Virus Replication

Merino-Ramos

Vázquez-Calvo

Casas

et al. 2016

Antimicrob Agents Chemother

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“…It has to be considered that neurons, which constitute a major target for WNV replication in the nervous system ( 53 ), are specially enriched in SM ( 22 ), which may also reinforce the relevance of this lipid's levels in WNV infection. Although increased levels of other lipids, such as cholesterol or ceramide, can also promote WNV multiplication in cultured cells ( 7,9 ), this possibility was excluded in ASMko mice because neither cholesterol nor ceramide are enriched in their brains ( 36 ). Considering all these factors, the results observed for ASMko mice provide solid evidence of the involvement of the SM pathway in WNV infection and in vivo pathogenesis.…”

Section: Discussionmentioning

confidence: 98%

“…Viruses can take advantage of these properties to develop specialized membrane sites for RNA replication and particle biogenesis ( 18 ). Lipidomic analyses have shown an increase in the content of both ceramide and SM in fl avivirusinfected cells ( 8,12 ), and ceramide has specifi cally been associated with WNV replication and viral particle biogenesis ( 8,9 ). Regarding SM, it is enriched in membranes from the replication complex of viruses phylogenetically related to WNV, such as dengue virus and hepatitis C virus ( 12,19 ).…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…In a parallel manner to that described for other fl aviviruses, both RNA replication and acquisition of lipid envelope are associated to specialized membranous structures derived from the endoplasmic reticulum (ER) ( 3-6 ). To generate this adequate environment for viral multiplication, WNV promotes the synthesis and accumulation of specifi c lipids (fatty acids, cholesterol, glycerophospholipids, and sphingolipids) within infected cells ( 5,(7)(8)(9). This selective manipulation of host cell lipid metabolism is not a unique feature of WNV infection, as it is also observed in cells infected with other fl aviviruses ( 10-12 ).…”

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Host sphingomyelin increases West Nile virus infection in vivo

Martín-Acebes

Gabandé‐Rodríguez

García-Cabrero

et al. 2016

Journal of Lipid Research

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The fl avivirus, West Nile virus (WNV), is a neurotropic enveloped plus-strand RNA virus transmitted through the bite of mosquitoes. This virus is responsible for recurrent outbreaks of febrile illness and meningoencephalitis worldwide, accounting for hundreds of human deaths every year ( 2 ). The WNV lifecycle is intimately associated to cellular lipids, and RNA replication and virion biogenesis are coupled into highly remodeled intracellular membranes ( 3, 4 ). In a parallel manner to that described for other fl aviviruses, both RNA replication and acquisition of lipid envelope are associated to specialized membranous structures derived from the endoplasmic reticulum (ER) ( 3-6 ). To generate this adequate environment for viral multiplication, WNV promotes the synthesis and accumulation of specifi c lipids (fatty acids, cholesterol, glycerophospholipids, and sphingolipids) within infected cells ( 5,(7)(8)(9). This selective manipulation of host cell lipid metabolism is not a unique feature of WNV infection, as it is also observed in cells infected with other fl aviviruses ( 10-12 ).Among the cellular lipids co-opted by WNV, sphingolipids merit special attention because they are particularly enriched in the nervous system, a major target tissue during WNV infection ( 13,14 ). Sphingolipids derive from sphingosine, a long-chain amino alcohol that is acylated with a long-chain fatty acid to give ceramide, which

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The role of brain innate immune response in lysosomal storage disorders: fundamental process or evolutionary side effect?

Vitner

2020

FEBS Letters

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Sphingolipidoses are diseases caused by mutations in genes responsible for sphingolipid degradation and thereby lead to sphingolipid accumulation. Most sphingolipidoses have a neurodegenerative manifestation characterized by innate immune activation in the brain. However, the role of the immune response in disease progression is ill-understood. In contrast to infectious diseases, immune activation is unable to eliminate the offending agent in sphingolipidoses resulting in ineffective, chronic inflammation. This paradox begs two fundamental questions: Why has this immune response evolved in sphingolipidoses? What role does it play in disease progression? Here, starting from the observation that sphingolipids (SLs) are elevated also in infectious diseases, I discuss the possibility that the activation of the brain immune response by SLs has evolved as a part of the immune response against pathogens and plays no major role in sphingolipidoses.

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Differential utilisation of ceramide during replication of the flaviviruses West Nile and dengue virus

Cited by 57 publications

References 45 publications

Modification of the Host Cell Lipid Metabolism Induced by Hypolipidemic Drugs Targeting the Acetyl Coenzyme A Carboxylase Impairs West Nile Virus Replication

Modification of the Host Cell Lipid Metabolism Induced by Hypolipidemic Drugs Targeting the Acetyl Coenzyme A Carboxylase Impairs West Nile Virus Replication

Host sphingomyelin increases West Nile virus infection in vivo

The role of brain innate immune response in lysosomal storage disorders: fundamental process or evolutionary side effect?

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