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、寨卡病毒等）和披膜病毒科 （基孔肯雅热等），通过幼稚雌性蚊子的血粉感染全世界约 4 亿人。 可能从感染者那里获得传染源（例如病毒），并将其传染给下一个人。 雌性蚊子的寻找宿主和吸血行为是病毒在体内传播的关键决定因素 哺乳动物的体味含有许多影响蚊子的挥发性化学物质。 其中一些是明显的蚊子引诱剂，这些线索因人而异。 人，并且具有同一人的生理条件，但是，是否蚊子仍然未知。 在最近的一项研究中，我们发现传播的病毒可以操纵宿主的气味来影响蚊子的行为。 登革热 (DENV) 和寨卡病毒 (ZIKV) 可以操纵哺乳动物宿主皮肤微生物群，产生有效的 蚊子引诱剂苯乙酮，这是因为病毒感染显着增加了苯乙酮的丰度。 皮肤芽孢杆菌是挥发性代谢物苯乙酮的主要生产者，其下调。 小鼠皮肤中抵抗素样杀菌抗菌肽 (AMP)、RELMα 的表达（约 25 倍）。 这些结果表明，DENV/ZIKV 可以增强其宿主对蚊子的吸引力，从而促进 然而，这些病毒如何抑制 RELMα 的表达尚不清楚。 表达（不是任何其他皮肤 AMP）需要膳食视黄醇（又名维生素 A），表明 DENV/ZIKV 可能干预视黄醇信号传导 视黄醇与视黄醇结合蛋白 4 (RBP4) 结合并由视黄醇转运。 细胞表面受体 STRA6，通过视黄醇脱氢酶 1 (RDH1) 转化为视黄醛，然后转化为视黄酸 视黄酸脱氢酶 1A (RALDH1A) 与视黄酸受体 (RAR) 结合。 进入细胞核并激活基因转录，包括 RELMα 和 RAR，有趣的是，口服给药。 视黄酸、异维A酸、恢复正常的 RELMα 表达和皮肤微生物稳态 DENV/ZIKV 感染的小鼠，表明 DENV/ZIKV 的目标是视黄醇和视黄酸之间的一个步骤。 我们的新数据表明 DENV/ZIKV 有效复制并抑制 RELMα 和 RAR 表达 在小鼠原代皮肤表皮角质形成细胞中，由视黄醇诱导，但不是由视黄醛或异维A酸诱导， 原代表皮细胞类型和 AMP 生产者 值得注意的是，基孔肯雅病毒不会抑制视黄醇信号传导。 因此，我们认为DENV/ZIKV干扰了视黄醇和视黄醛之间的一个步骤 为此，我们将查明DENV/ZIKV靶向的视黄醇途径的步骤，并确定其作用途径。 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。 途径和 RELMα 在皮肤中的表达这些结果可适用于其他蚊媒传播。 黄病毒并为深入的机制研究奠定基础。