The mechanism of flaviviral suppression of vitamin A metabolism

蚊媒病毒，主要包括黄病毒科(登革热、寨卡病毒等)和Togaviridae (基孔肯雅热等)，全世界约有4亿人感染。通过一顿血饭，一只天真的雌性蚊子 可能从感染者那里获得感染性病原体(例如病毒)，并将其传染给下一个人。因此， 雌性蚊子的寻找宿主和觅血行为是病毒传播的关键决定因素 大自然。哺乳动物的体臭含有许多挥发性化合物，这些化合物会影响蚊子的 行为。其中一些是很好的蚊子引诱剂。这些暗示因人而异 人，并与同一人的生理条件。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，我们发现 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，产生一种有效的 蚊子引诱剂苯乙酮。这是因为病毒感染显著增加了病毒的丰度 皮肤芽孢杆菌是苯乙酮作为挥发性代谢物的主要产生者。DENV/ZIKV下调 (~25倍)抵抗素样杀菌抗菌肽(AMP)在小鼠皮肤中的表达，RELmα。 这些结果表明，DENV/ZIKV可以增强其对蚊子的寄主引诱作用，从而促进 他们的传输。然而，这些病毒如何抑制RELmα的表达尚不清楚。本构RELmα 表达(不是任何其他皮肤AMP)需要饮食中的视黄醇(也就是维生素A)，这表明DENV/ZIKV 可能会干预视黄醇信号。视黄醇与视黄醇结合蛋白4(RBP4)结合，并通过 细胞表面受体STRA6被视黄醇脱氢酶1(RDH1)转化为视黄醛，然后转化为维甲酸 由视黄醛脱氢酶1A(RALDH1A)产生的酸。视黄酸与视黄酸受体(RARs)结合 进入细胞核，激活基因转录，包括α和RARs。有趣的是，口服给药 维甲酸，异维甲酸，恢复正常的α表达和皮肤微生物动态平衡 DENV/ZIKV感染的小鼠，表明DENV/ZIKV的靶点在视黄醇和维甲酸之间。的确， 我们的新数据表明，DENV/ZIKV能够有效复制并抑制RELmα和RAR的表达 由视黄醇而不是由视黄醛或异维A酸诱导的小鼠原代皮肤表皮角质形成细胞 初级表皮细胞类型和AMP的产生者。值得注意的是，基孔肯雅病毒并不抑制视黄醇信号。 因此，我们假设DENV/ZIKV干扰视黄醇和视黄醇的视黄醛之间的一个步骤 路径。为此，我们将精确定位DENV/ZIKV靶向的视黄醇途径的步骤，并确定 抑制视黄醇途径的病毒蛋白(S)。我们将讨论这些黄病毒是如何抑制视黄醇的 途径和α在皮肤中的表达。这些结果可能也适用于其他蚊媒传播的 为深入的机理研究奠定了基础。

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.