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)和披膜病毒科
(基孔肯雅热等),感染了全球大约4亿人。一只天真的雌蚊子,
可能获得感染因子(例如,病毒)从受感染的人,并将其传递给下一个人。因此,我们建议,
雌蚊的寄主寻找和吸血行为是病毒在体内循环的关键决定因素,
自然哺乳动物的体臭中含有许多挥发性化合物,
行为。其中一些是特征良好的蚊子引诱剂。这些线索因人而异
一个人,和同一个人的生理条件。然而,目前还不清楚蚊子是否-
传播的病毒可以操纵宿主的气味来影响蚊子的行为。在最近的一项研究中,
登革热(DENV)和寨卡病毒(ZIKV)可以操纵它们的哺乳动物宿主皮肤微生物群,
蚊子引诱剂苯乙酮。这是因为病毒感染显著增加了
皮肤芽孢杆菌属细菌,苯乙酮作为挥发性代谢产物的主要生产者。DENV/ZIKV下调
小鼠皮肤中抵抗素样杀菌抗菌肽(AMP)RELMα的表达增加约25倍。
这些结果表明,DENV/ZIKV可以增强其对蚊子的宿主吸引力,从而促进蚊子的繁殖。
他们的传输。然而,这些病毒如何抑制RELMα表达尚不清楚。本构RELMα
表达(而不是任何其他皮肤AMP)需要膳食视黄醇(又名维生素A),这表明DENV/ZIKV
可能会干扰视黄醇信号。视黄醇与视黄醇结合蛋白4(RBP 4)结合,并通过一种
细胞表面受体STRA 6,通过视黄醇脱氢酶1(RDH 1)转化为视黄醇,然后转化为视黄酸
视黄醛脱氢酶1A(RALDH 1A)。视黄酸结合视黄酸受体(RAR),
进入细胞核并激活基因转录,包括RELMα和RAR。有趣的是,
维甲酸,异维甲酸,恢复了正常的RELMα表达和皮肤微生物的稳态,
这表明DENV/ZIKV靶向视黄醇和视黄酸之间的步骤。的确,
我们的新数据显示,DENV/ZIKV复制富有成效,并抑制RELMα和RAR表达,
在小鼠原代皮肤表皮角质形成细胞中,
初级表皮细胞类型和AMP的生产者。值得注意的是,基孔肯雅病毒没有抑制视黄醇信号。
因此,我们假设DENV/ZIKV干扰视黄醇和视黄醇醛之间的步骤,
通路为此,我们将精确定位DENV/ZIKV靶向的视黄醇途径的步骤,并鉴定其在DENV/ZIKV中的作用。
抑制视黄醇途径的病毒蛋白。我们将讨论这些黄病毒如何抑制视黄醇
皮肤中的RELMα表达。这些结果可能适用于其他蚊媒
为深入研究黄病毒的作用机制奠定了基础。
项目成果
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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
- 批准号:
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
白介素22在小鼠西尼罗病毒发病机制中的作用
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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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