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： 在过去的十年中，美国的媒介疾病病例数量增加了两倍 包括蚊子传播的寨卡病毒（ZIKV）在内的病原体仍然对普通公共卫生有明显的威胁。这 ZIKV在美洲和东南亚的爆发是全球主要的健康问题，主要是由于 与产前感染导致的胎儿颅颅异常和畸形有关。虽然 怀孕期间的ZIKV感染随便与小头畸形有关，重要的是要注意颅内 钙化是ZIKV阳性婴儿中最常见的异常。实际上，磁共振 巴西大型ZIKV阳性婴儿队列的成像研究报告说，颅内钙化是最大的 常见的临床观察。钙化发生在软组织中，但钙异常 大脑不仅严重影响运动功能，语音能力和视力，而且会引起癫痫发作。尽管有 然而，ZIKV诱导的钙化及其潜在的可怕结果的临床证据不断增长。 ZIKV诱导的脑钙化的分子机制仍然难以捉摸。我的初步观察 ZIKV人胎儿脑标本表明，高水平的钙沉积物与病毒感染 血管周细胞。有趣的是，脑血管周围和成骨前体细胞的ZIKV感染稳健 体外诱导钙化。令人惊讶的是，钙化的诱导特定于亚洲ZIKV 菌株，但不是非洲ZIKV菌株。非洲ZIKV菌株迅速复制，诱导细胞死亡，而亚洲 ZIKV菌株持续复制，导致异常的钙沉积。令人惊讶的是，zikv表达式库 屏幕显示NS3蛋白酶足以诱导钙化。基于这些初步数据，我 假设ZIKV靶向特定的宿主脑周围细胞，并利用NS3蛋白酶诱导 颅内钙化，最终导致与病毒相关的先天性异常。 在此，我试图解决以下问题：（i）哪些宿主细胞针对ZIKV诱导的钙化，， （ii和iii）哪些以及ZIKV NS3蛋白酶在感染过程中如何触发异常钙化。这个建议 具有高度创新性和翻译性，并有可能为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。