Zika Virus Cell Tropism and Pathogenesis in the Developing Inner Ear

发育中的内耳中的寨卡病毒细胞趋向性和发病机制

• 批准号: 9430822
• 负责人: Donna M Fekete
• 金额: $ 21.8万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-21 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9430822
• 关键词: Adult; Aedes; Affect; Anatomy; Animal Model; Apoptosis; Area; Auditory; Biological Assay; Blocking Antibodies; Brain; Cell Death; Cell Maturation; Cell Proliferation; Cell Survival; Cell division; Cells; Cellular Tropism; Central America; Chickens; Child; Cochlea; Congenital Abnormality; Culicidae; Data; Defect; Development; Disease Outbreaks; Embryo; Emergency Situation; Epithelium; Etiology; Exanthema; Family; Fetus; First Pregnancy Trimester; Flavivirus; Ganglia; Gene Expression; Genetic; Guillain-Barré Syndrome; Hair Cells; Health; Hearing; Hearing problem; Homologous Gene; Human; In Vitro; Infant; Infection; Injectable; Injection of therapeutic agent; Innate Immune Response; Innate Immune System; International; Knowledge; Label; Labyrinth; Link; Long-Term Effects; Maintenance; Mesenchyme; Microcephaly; Morphogenesis; Morphology; Mothers; Mus; Natural Immunity; Natural regeneration; Neonatal; Neurodevelopmental Impairment; Neurons; Newborn Infant; Organ; Organ of Corti; Outcome; Pathogenesis; Pathologic; Pathology; Pathway interactions; Perinatal; Peripheral; Pregnancy; Pregnant Women; Production; Reporter; Reporting; Retinal Diseases; Risk; Role; Secondary to; Sensorineural Hearing Loss; Sensory; South America; Stria Vascularis; Supporting Cell; Symptoms; Tegmentum Mesencephali; Tilia; Time; Tissues; Transgenic Organisms; Tropism; Uganda; Virus; Virus Diseases; Work; World Health Organization; Zika Virus; auditory pathway; base; brain abnormalities; cell type; clinically significant; equilibration disorder; experimental study; forest; hearing impairment; in utero; in vivo Model; innovation; insight; interest; mechanotransduction; nerve stem cell; nervous system development; nervous system disorder; neuroblast; otoacoustic emission; otoconia; postnatal; prenatal; prenatal exposure; progenitor; response; virus tropism

The Zika virus (ZIKV) of the flaviviridae family of viruses poses a significant threat to the health of newborn infants and young children. ZIKV infection predominantly affects the development of the nervous system and its neurotopism has been well-established. In September 2016, ZIKV was linked to sensorineural hearing loss in newborn infants that were prenatally exposed, but essentially nothing is known about where the developmental pathologies lie in the auditory pathway. Reports of abnormal otoacoustic emissions in ZIKV-exposed infants suggest that at least some of the sensorineural defects may originate within the cochlea, the auditory organ of the inner ear. This study will focus on correlating the timing of ZIKV exposure at embryonic and perinatal stages to the types of inner ear cells that become infected, using two animal models (chicken and mice). Preliminary data show that ZIKV can infect the cochlea, in particular the sensory domain, the stria vascularis (tegmentum vasculosum in the chicken cochlea) and the auditory ganglion. The proposed studies will involve delivery of ZIKV directly to the embryonic inner ear and the cochlea to assess cellular tropism and otic pathogenesis associated with ZIKV. Aim 1 will determine the cellular tropism and timing of ZIKV infection in ovo by direction injection of virus into the chicken otocyst from embryonic day (E) 3–5. Virus distribution, cell proliferation, apoptosis, and gene expression related to innate immune responses will be assayed several days after infection. Aim 2 will determine the cellular tropism and timing of ZIKV infection in vitro in embryonic (E12.5, E15.5) and neonatal (postnatal day 1) mouse cochlea cultures. Genetic labeling of hair cells, supporting cells, or intermediate cells of the stria vascularis will aid in following the fates of these cell types for up to 6 days in culture. Virus distribution, cell proliferation, apoptosis, hair cell ultrastructure, and hair cell mechanotransduction will be evaluated several days after ZIKV exposure. Antibody blocking experiments will be used to explore the role of the periotic mesenchyme as a direct target of ZIKV. These studies should aid in understanding how ZIKV infection of the developing sensory periphery might contribute to sensorineural hearing loss in human infants.

寨卡病毒（ZIKV）属于黄病毒科病毒，对新生儿的健康构成重大威胁 婴幼儿。ZIKV感染主要影响神经系统的发育， 神经异位症已经得到了很好的证实。2016年9月，ZIKV与感觉神经性听力损失有关， 出生前暴露的新生儿，但基本上不知道发育 病理学在于听觉通路。ZIKV暴露婴儿异常耳声发射的报告 这表明，至少有一些感觉神经缺陷可能起源于耳蜗，听觉器官， 内耳本研究将集中于将胚胎和围产期阶段ZIKV暴露的时间与胚胎和围产期阶段的ZIKV暴露的时间相关联。 通过两种动物模型（鸡和小鼠），研究内耳细胞的感染类型。初步 数据显示ZIKV可以感染耳蜗，特别是感觉域，血管纹（被盖 鸡耳蜗中的血管）和听神经节。拟议的研究将涉及ZIKV的递送 直接接触胚胎内耳和耳蜗，以评估细胞向性和与耳发病机制相关的 关于ZIKV目的1将通过直接注射ZIKV来确定卵内ZIKV感染的细胞向性和时间。 病毒从胚胎第3-5天进入鸡耳囊。病毒分布、细胞增殖、凋亡和 在感染后几天测定与先天免疫应答相关的基因表达。目标2将 在胚胎（E12.5，E15.5）和新生儿中体外确定ZIKV感染的细胞向性和时间 （出生后第1天）小鼠耳蜗培养物。毛细胞、支持细胞或中间细胞的遗传标记 血管纹将有助于跟踪这些细胞类型在培养物中长达6天的命运。病毒分布， 细胞增殖、细胞凋亡、毛细胞超微结构和毛细胞机械转导将进行几项评估 在ZIKV暴露后几天。抗体阻断实验将用于探索牙周膜的作用， 间充质细胞作为ZIKV的直接靶标。这些研究应该有助于理解ZIKV感染是如何影响人类的免疫系统的。 发育中的感觉周边可能导致人类婴儿的感音神经性听力损失。