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Zika Virus Infection Induces DNA Damage Response and S-Phase Arrest in Human Cortical Neural Progenitors

Title: Zika Virus Infection Induces DNA Damage Response and S-Phase Arrest in Human Cortical Neural Progenitors.
Name(s): Hammack, Christy, author
Tang, Hengli, professor directing dissertation
Megraw, Timothy L., university representative
Chadwick, Brian P., committee member
Gilbert, David M., committee member
Li, Yan, committee member
Zhu, Fanxiu, committee member
Florida State University, degree granting institution
College of Arts and Sciences, degree granting college
Department of Biological Science, degree granting department
Type of Resource: text
Genre: Text
Doctoral Thesis
Issuance: monographic
Date Issued: 2018
Publisher: Florida State University
Place of Publication: Tallahassee, Florida
Physical Form: computer
online resource
Extent: 1 online resource (117 pages)
Language(s): English
Abstract/Description: Zika virus (ZIKV) is a re-emerging mosquito-borne flavivirus of significant public health concern closely related to other highly pathogenic flaviviruses, such as dengue virus (DENV) and West Nile virus (WNV). With the rise of ZIKV in Brazil in 2015, its potential link to microcephaly and other severe neurological birth defects prompted the World Health Organization to declare ZIKV a Public Health Emergency of International Concern. Since this time, numerous studies have provided ample evidence to establish ZIKV as the causative agent of microcephaly, yet the molecular mechanisms underlying these neurodevelopmental defects are not well understood. We therefore establish a tractable experimental model system to investigate the impact of ZIKV on human neural development. We demonstrate that ZIKV efficiently infects human cortical neural progenitor cells (hNPCs) derived from induced pluripotent stem cells, but less efficiently infects other cells along the neural differentiation pathway, including immature cortical neurons. Infected hNPCs further release infectious ZIKV particles. Importantly, ZIKV infection disrupts cell cycle progression and induces cell death in hNPCs contributing to their attenuated growth. Global transcriptome analyses of ZIKV-infected hNPCs reveal transcriptional dysregulation, notably a downregulation of cell-cycle-related genes, highlighting the potential involvement of cell cycle pathways in ZIKV biology. We then study the molecular mechanisms by which ZIKV manipulates the cell cycle in hNPCs and the functional consequences of cell-cycle perturbation on the replication of ZIKV and related flaviviruses. We demonstrate that host cell-cycle disruption is unique to ZIKV among the flaviviruses tested, including DENV and WNV, however similar among the two strains of ZIKV tested, including the prototype Uganda strain and a Puerto Rican strain. ZIKV, but not DENV, infection induces DNA double-strand breaks, triggering the DNA damage response through the ATM/Chk2 signaling pathway, while suppressing activation of the ATR/Chk1 signaling pathway in hNPCs. Furthermore, ZIKV infection impedes the progression of cells through S phase thereby preventing the completion of host DNA replication. Recapitulating the S-phase arrest state with S-phase inhibitors leads to an increase in ZIKV replication, but not of WNV or DENV replication. Together, our results identify hNPCs as a direct target of ZIKV and the damaging impact of ZIKV on the growth of hNPCs. Importantly, our data demonstrate ZIKV’s ability to induce host DNA damage and arrest cell cycle progression, which results in a cellular environment favorable for its replication. As hNPCs generate the cortical neurons during early fetal brain development, the ZIKV-mediated growth retardation likely contributes to the neurodevelopmental defects of the congenital Zika syndrome.
Identifier: 2018_Sp_Hammack_fsu_0071E_14286 (IID)
Submitted Note: A Dissertation submitted to the Department of Biological Science in partial fulfillment of the requirements for the degree of Doctor of Philosophy.
Degree Awarded: Spring Semester 2018.
Date of Defense: January 23, 2018.
Bibliography Note: Includes bibliographical references.
Advisory Committee: Hengli Tang, Professor Directing Dissertation; Timothy Megraw, University Representative; Brian P. Chadwick, Committee Member; David M. Gilbert, Committee Member; Yan Li, Committee Member; Fanxiu Zhu, Committee Member.
Subject(s): Cytology
Molecular biology
Persistent Link to This Record:
Host Institution: FSU

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Hammack, C. (2018). Zika Virus Infection Induces DNA Damage Response and S-Phase Arrest in Human Cortical Neural Progenitors. Retrieved from