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: 10618399
• 负责人: Weiqiang Chen
• 金额: $ 24.9万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618399
• 关键词: Address; Affect; African; Americas; Asian; Blood Vessels; Bone Morphogenetic Proteins; Brain; Calcium; Calvaria; Cell Death Induction; Cell physiology; Cells; Clinical; Collaborations; Congenital Abnormality; Craniofacial Abnormalities; Craniosynostosis; 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; 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 Factor beta; Uganda; Vector-transmitted infectious disease; Viral Genes; Viral Proteins; Virus; Vision; ZIKV infection; Zika Virus; brain cell; brain tissue; calcification; calcium phosphate; cell type; cohort; craniofacial; craniofacial tissue; cranium; fetal; global health; human fetal brain; human fetus 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.

项目摘要/摘要： 在过去的十年里，美国媒介传播疾病病例的数量增加了两倍，而这些 病原体，包括蚊媒寨卡病毒(ZIKV)，仍然是对公众健康的明显威胁。这个 美洲和东南亚的ZIKV疫情是一个主要的全球卫生问题，主要是由于 与胎儿头面部异常和畸形有关，由产前感染引起。虽然 妊娠期间寨卡病毒感染与小头畸形症很容易相关，值得注意的是，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阳性婴儿队列的影像研究报告最多的是颅内钙化 常见的临床观察。虽然钙化发生在软组织中，但体内钙的异常沉积 大脑不仅严重影响运动功能、言语能力和视力，还会导致癫痫发作。尽管 越来越多的临床证据表明ZIKV诱导的钙化及其潜在的可怕后果，然而，其病因 ZIKV诱导的脑钙化的分子机制仍然不清楚。我的初步观察是在 ZIKV人胎脑标本显示高水平的钙沉积存在于病毒感染的局部 血管周围细胞。耐人寻味的是，ZIKV感染脑血管周围和成骨前体细胞 体外诱导钙化。令人惊讶的是，钙化的诱导是亚洲ZIKV特有的 对非洲ZIKV毒株没有影响。非洲ZIKV毒株迅速复制，导致细胞死亡，而亚洲 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 筛选表明，NS3蛋白酶足以诱导钙化。根据这些初步数据，我 假设ZIKV靶向特定宿主脑血管周围细胞并利用NS3蛋白酶诱导 颅内钙化，最终导致病毒相关的先天性异常。 在这里，我试图解决以下问题：(I)哪些宿主细胞是ZIKV诱导的钙化的靶细胞， 以及(II和III)在感染过程中，哪些ZIKV NS3蛋白酶以及如何触发异常钙化。这项建议 具有很高的创新性和转化性，并可能为ZIKV诱导的颅内钙化提供新的见解 这是感染病毒的婴儿中出现的最常见的异常。