Molecular regulatory mechanism of Zika virus-induced intracranial calcifications

寨卡病毒诱导颅内钙化的分子调控机制

• 批准号: 10293610
• 负责人: Weiqiang Chen
• 金额: $ 9.4万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10293610
• 关键词: Address; Affect; African; Americas; Asians; Bone Morphogenetic Proteins; Brain; Calcium; Calvaria; Cell Death; Cell physiology; Cells; Clinical; Collaborations; Congenital Abnormality; Craniofacial Abnormalities; Craniosynostosis; Crystallization; Data; Defect; Deposition; Deterioration; Differentiated Gene; Disease Outbreaks; Etiology; Expression Library; Fetus; Future; Gene Expression; General Population; Genes; Human; Immunocompetent; Immunohistochemistry; Implant; In Vitro; Individual; Infection; Joint structure of suture of skull; Knock-in; Knock-in Mouse; Lentivirus Vector; Magnetic Resonance Imaging; Mass Spectrum Analysis; Mediating; Mesenchyme; Microcephaly; Molecular; Motor; Mus; Neurologic; Osteogenesis; Outcome; Pathology; Peptide Hydrolases; Pericytes; Phase; Phenotype; Physiological; Play; Pregnancy; Prevention strategy; Primary Infection; Process; Proteins; Public Health; Reporting; Role; Seizures; Signal Pathway; Signal Transduction; Signaling Protein; Southeastern Asia; Specimen; Speech; Surgical sutures; Technology; Testing; Therapeutic Intervention; Transforming Growth Factors; Uganda; Vector-transmitted infectious disease; Viral Genes; Viral Proteins; Virus; Vision; ZIKV infection; Zika Virus; base; brain cell; calcification; calcium phosphate; cell type; cohort; craniofacial; craniofacial tissue; cranium; fetal; global health; human fetal brain; human fetal brain tissue; imaging study; in vivo; innovation; insight; lentivirally transduced; mosquito-borne; mutant; osteogenic; pathogen; pre-clinical; precursor cell; premature; prenatal; protein purification; pup; radiological imaging; reverse genetics; single-cell RNA sequencing; soft tissue; spastic paralysis; stem cells; suture fusion; therapeutic development; therapeutic target; transcription factor

Project Summary/Abstract: The number of vector-borne disease cases in the US has tripled over the past decade and these pathogens including mosquito-borne Zika virus (ZIKV) remain an apparent threat to general public health. The ZIKV outbreaks in the Americas and Southeast Asia is a major global health concern, largely due to the association with fetal craniofacial abnormalities and malformations, resulting from prenatal infection. Although ZIKV infection during pregnancy is casually associated with microcephaly, it is important to note that intracranial calcification is the most frequent abnormality present in ZIKV-positive babies. In fact, Magnetic Resonance Imaging study of Brazilian large ZIKV-positive baby cohort reported the intracranial calcifications as the most common clinical observations. While calcification occurs in soft tissues, the abnormal deposition of calcium in brain not only severely affects motor function, speech ability, and vision, but also causes seizures. Despite the growing clinical evidences of ZIKV-induced calcifications and their potential dire outcomes, however, the etiology and molecular mechanisms of ZIKV-induced brain calcification remain elusive. My preliminary observations in ZIKV human fetal brain specimens showed that high level of calcium deposits was localized with virus-infected perivascular cells. Intriguingly, ZIKV-infection of brain perivascular and osteogenic precursor cells robustly induced calcifications in vitro. Surprisingly, the induction of calcification was lineage-specific to the Asian ZIKV strains, but not to the African ZIKV strains. African ZIKV strains rapidly replicated, inducing cell death, while Asian ZIKV strains persistently replicated, leading to aberrant calcium deposition. Surprisingly, ZIKV expression library screen showed that NS3 protease was sufficient to induce calcification. Based on these preliminary data, I hypothesize that ZIKV targets specific host brain perivascular cells and utilizes NS3 protease to induce intracranial calcifications, which ultimately contributes to virus-associated congenital abnormality. Herein, I seek to address the following questions: (i) which host cells are targeted for ZIKV-induced calcifications, and (ii and iii) which and how ZIKV NS3 protease triggers abnormal calcification during infection. This proposal is highly innovative and translational, and potentially shed new insights to ZIKV-induced intracranial calcification that is the most frequent abnormality present in virus-infected babies.

项目概要/摘要： 在过去十年中，美国媒介传播疾病的病例数量增加了两倍， 包括蚊媒寨卡病毒（ZIKV）在内的病原体仍然对公众健康构成明显威胁。的 美洲和东南亚的ZIKV爆发是一个主要的全球健康问题，这主要是由于 与产前感染引起的胎儿颅面异常和畸形有关。虽然 妊娠期间的ZIKV感染与小头畸形偶然相关，重要的是要注意颅内 钙化是ZIKV阳性婴儿中最常见的异常。事实上，磁共振 巴西大型ZIKV阳性婴儿队列的成像研究报告颅内钙化是最常见的 常见的临床观察。当钙化发生在软组织中时， 大脑不仅会严重影响运动功能、语言能力和视力，还会导致癫痫发作。尽管 越来越多的ZIKV诱导的钙化及其潜在可怕后果的临床证据，然而， ZIKV诱导的脑钙化的分子机制仍然难以捉摸。我的初步意见是， ZIKV人胎脑标本显示，高水平的钙沉积位于病毒感染的脑组织中。 血管周围细胞有趣的是，脑血管周围和成骨前体细胞的ZIKV感染 体外诱导钙化。令人惊讶的是，钙化的诱导对于亚洲ZIKV是谱系特异性的。 菌株，但不是非洲ZIKV菌株。非洲ZIKV病毒株迅速复制，诱导细胞死亡，而亚洲ZIKV病毒株迅速复制，诱导细胞死亡。 ZIKV毒株持续复制，导致异常钙沉积。令人惊讶的是，ZIKV表达文库 筛选显示NS 3蛋白酶足以诱导钙化。根据这些初步数据，我 假设ZIKV靶向特异性宿主脑血管周围细胞并利用NS 3蛋白酶诱导 颅内钙化，最终导致病毒相关的先天性异常。 本文中，我试图解决以下问题：（i）哪些宿主细胞被靶向ZIKV诱导的钙化， 和（ii和iii）在感染期间哪种ZIKV NS 3蛋白酶以及如何触发异常钙化。这项建议 具有高度创新性和转化性，并可能为ZIKV诱导的颅内钙化提供新的见解 这是病毒感染婴儿中最常见的异常。