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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结/文摘: