Western Zika Virus in Human Fetal Neural Progenitors Persists Long Term with Partial Cytopathic and Limited Immunogenic Effects.
The recent Zika virus (ZIKV) outbreak in the Western hemisphere is associated with severe pathology in newborns, including microcephaly and brain damage. The mechanisms underlying these outcomes are under intense investigation. Here, we show that a 2015 ZIKV isolate replicates in multiple cell types, including primary human fetal neural progenitors (hNPs). In immortalized cells, ZIKV is cytopathic and grossly rearranges endoplasmic reticulum membranes similar to other flaviviruses. In hNPs, ZIKV infection has a partial cytopathic phase characterized by cell rounding, pyknosis, and activation of caspase 3. Despite notable cell death, ZIKV did not activate a cytokine response in hNPs. This lack of cell intrinsic immunity to ZIKV is consistent with our observation that virus replication persists in hNPs for at least 28 days. These findings, supported by published fetal neuropathology, establish a proof-of-concept that neural progenitors in the developing human fetus can be direct targets of detrimental ZIKV-induced pathology.
Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Division of Infectious Disease, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Natasha W
NW
Hanners
Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Jennifer L
JL
Eitson
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Noriyoshi
N
Usui
Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
R Blake
RB
Richardson
Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Eric M
EM
Wexler
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Genevieve
G
Konopka
Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: john.schoggins@utsouthwestern.edu.
John W
JW
Schoggins
D002460:Cell Line; D003588:Cytopathogenic Effect, Viral / Q000276:immunology*; D005333:Fetus / Q000473:pathology*; D006801:Humans; D058953:Neural Stem Cells / Q000276:immunology* / Q000821:virology*; D013997:Time Factors; D014779:Virus Replication; D000071244:Zika Virus / Q000276:immunology* / Q000302:isolation & purification / Q000502:physiology / Q000648:ultrastructure; D000071243:Zika Virus Infection / Q000276:immunology* / Q000821:virology*