The mechanism of flaviviral suppression of vitamin A metabolism

黄病毒抑制维生素A代谢的机制

• 批准号: 10711672
• 负责人: PENGHUA WANG
• 金额: $ 20.75万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10711672
• 关键词: Accounting; Acetone; Acetophenones; Affect; All-Trans-Retinol; Ammonia; Arboviruses; Bacillus; Bacteria; Behavior; Binding; Blood; Carbon Dioxide; Cell Nucleus; Cell Surface Receptors; Cells; Cessation of life; Chemicals; Chikungunya virus; Circulation; Country; Cues; Culicidae; Data; Dengue; Dengue Fever; Dengue Virus; Epidermis; Esters; Family; Feeding behaviors; Female; Flaviviridae; Flavivirus; Foundations; Genetic Transcription; High Pressure Liquid Chromatography; Homeostasis; Human; Individual; Infection; Infectious Agent; Isotretinoin; Lactic acid; Lentivirus Vector; Mass Spectrum Analysis; Metabolism; Motivation; Mus; Nature; Odors; Oral Administration; Pathway interactions; Patients; Persons; Physiological; Productivity; Proteins; RBP4 gene; Retinaldehyde; Retinoic Acid Binding; Retinoic Acid Receptor; Retinoids; Retinol dehydrogenase; Signal Transduction; Skin; Togaviridae; Tretinoin; Venezuelan Equine Encephalomyelitis; Viral Proteins; Virus; Virus Diseases; Vitamin A; Volatilization; West Nile; Yellow Fever; ZIKA; ZIKV infection; Zika Virus; antimicrobial peptide; arboviral disease; bactericide; cell type; chikungunya; dietary requirement; keratinocyte; microbial; mosquito reproduction; mosquito-borne; receptor expression; resistin; response; retinaldehyde dehydrogenase; skin microbiome; skin microbiota; transmission process; uptake; viral transmission

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。