The mechanism of flaviviral suppression of vitamin A metabolism
黄病毒抑制维生素A代谢的机制
基本信息
- 批准号:10711672
- 负责人:
- 金额:$ 20.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-19 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AccountingAcetoneAcetophenonesAffectAll-Trans-RetinolAmmoniaArbovirusesBacillusBacteriaBehaviorBindingBloodCarbon DioxideCell NucleusCell Surface ReceptorsCellsCessation of lifeChemicalsChikungunya virusCirculationCountryCuesCulicidaeDataDengueDengue FeverDengue VirusEpidermisEstersFamilyFeeding behaviorsFemaleFlaviviridaeFlavivirusFoundationsGenetic TranscriptionHigh Pressure Liquid ChromatographyHomeostasisHumanIndividualInfectionInfectious AgentIsotretinoinLactic acidLentivirus VectorMass Spectrum AnalysisMetabolismMotivationMusNatureOdorsOral AdministrationPathway interactionsPatientsPersonsPhysiologicalProductivityProteinsRBP4 geneRetinaldehydeRetinoic Acid BindingRetinoic Acid ReceptorRetinoidsRetinol dehydrogenaseSignal TransductionSkinTogaviridaeTretinoinVenezuelan Equine EncephalomyelitisViral ProteinsVirusVirus DiseasesVitamin AVolatilizationWest NileYellow FeverZIKAZIKV infectionZika Virusantimicrobial peptidearboviral diseasebactericidecell typechikungunyadietary requirementkeratinocytemicrobialmosquito reproductionmosquito-bornereceptor expressionresistinresponseretinaldehyde dehydrogenaseskin microbiomeskin microbiotatransmission processuptakeviral transmission
项目摘要
Mosquito-borne viruses, primarily including families of Flaviviridae (dengue, Zika etc.) and Togaviridae
(Chikungunya etc.), infect roughly ~400 million people worldwide. By a blood meal, a naïve female mosquito
may acquire an infectious agent (e.g., virus) from an infected person, and pass it on to next person. Therefore,
the host-seeking and blood-feeding behavior of female mosquitoes is a key determinant of virus circulation in
nature. The mammalian body odors contain many volatile chemical compounds that influence mosquitoes’
behaviors. Some of these are well-characterized mosquito attractants. These cues vary from a person to another
person, and with the physiological conditions of the same person. However, it remains unknown if mosquito-
transmitted viruses can manipulate their host odors to influence mosquito behaviors. In a recent study, we found
that dengue (DENV) and Zika (ZIKV) can manipulate their mammalian host skin microbiota to produce a potent
mosquito attractant, acetophenone. This was because viral infection significantly increased the abundance of
skin Bacillus bacteria, the major producer of acetophenone as a volatile metabolite. DENV/ZIKV downregulated
(~25-fold) the expression of a resistin-like bactericidal antimicrobial peptide (AMP), RELMα, in the mouse skin.
These results demonstrate that DENV/ZIKV can enhance their host attractiveness to mosquitoes, thus facilitate
their transmission. However, how these viruses inhibit RELMα expression is unknown. Constitutive RELMα
expression (not any other skin AMPs) requires dietary retinols (a.k.a vitamin A), suggesting that DENV/ZIKV
likely intervenes retinol signaling. Retinols are bound by retinol binding protein 4 (RBP4) and transported by a
cell surface receptor STRA6, converted into retinaldehydes by retinol dehydrogenase 1 (RDH1), then to retinoic
acids by retinaldehyde dehydrogenase 1A (RALDH1A). Retinoic acids bind retinoic acid receptors (RARs), which
enter the nucleus and activate gene transcription, including RELMα and RARs. Intriguingly, oral administration
of a retinoic acid, isotretinoin, restored normal RELMα expression and skin microbial homeostasis to
DENV/ZIKV-infected mice, suggesting that DENV/ZIKV target a step between retinol and retinoic acid. Indeed,
our new data showed that DENV/ZIKV replicated productively and suppressed RELMα and RAR expression
induced by retinol, but not by retinaldehyde or isotretinoin in mouse primary skin epidermal keratinocytes, the
primary epidermal cell type and producer of AMPs. Of note, the Chikungunya virus did not inhibit retinol signaling.
Therefore, we hypothesize that DENV/ZIKV interferes with a step between retinol and retinaldehyde of the retinol
pathway. To this end, we will pinpoint the step of the retinol pathway targeted by DENV/ZIKV, and identify the
viral protein (s) that suppress the retinol pathway. We will address how these flaviviruses suppress the retinol
pathway and RELMα expression in the skin. These results could be applicable to other mosquito-borne
flaviviruses and lay a foundation for in-depth mechanistic studies.
蚊媒病毒,主要包括黄病毒科(登革热、寨卡等)和托加病毒科
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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PENGHUA WANG其他文献
PENGHUA WANG的其他文献
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{{ truncateString('PENGHUA WANG', 18)}}的其他基金
A critical role for UBXN3B in IgG homeostasis and maternal transfer
UBXN3B 在 IgG 稳态和母体转移中的关键作用
- 批准号:
10302314 - 财政年份:2020
- 资助金额:
$ 20.75万 - 项目类别:
A critical role of NLRP6 in West Nile virus pathogenesis in mice
NLRP6 在小鼠西尼罗河病毒发病机制中的关键作用
- 批准号:
8635669 - 财政年份:2014
- 资助金额:
$ 20.75万 - 项目类别:
A critical role of NLRP6 in West Nile virus pathogenesis in mice
NLRP6 在小鼠西尼罗河病毒发病机制中的关键作用
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8835026 - 财政年份:2014
- 资助金额:
$ 20.75万 - 项目类别:
The role of interleukin 22 in West Nile virus pathogenesis in mice
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$ 20.75万 - 项目类别:
The role of interleukin 22 in West Nile virus pathogenesis in mice
白介素22在小鼠西尼罗病毒发病机制中的作用
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8444925 - 财政年份:2013
- 资助金额:
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