Zika Virus Infection Induces Cranial Neural Crest Cells to Produce Cytokines at Levels Detrimental for Neurogenesis.
Zika virus (ZIKV) infection during pregnancy is linked to microcephaly, which is attributed to infection of developing brain structures. ZIKV infects neural progenitor cells in vitro, though its effects on other developmentally relevant stem cell populations, including cranial neural crest cells (CNCCs), have not been assessed. CNCCs give rise to most cranial bones and exert paracrine effects on the developing brain. Here, we report that CNCCs are productively infected by ZIKV, but not by the related dengue virus. ZIKV-infected CNCCs undergo limited apoptosis but secrete cytokines that promote death and drive aberrant differentiation of neural progenitor cultures. Addition of two such cytokines, LIF or VEGF, at levels comparable to those secreted by ZIKV-infected CNCCs is sufficient to recapitulate premature neuronal differentiation and apoptotic death of neural progenitors. Thus, our results suggest that CNCC infection by ZIKV may contribute to associated embryopathies through signaling crosstalk between developing face and brain structures.
Stanford Immunology, Stanford School of Medicine, Stanford University, Stanford, CA 94305, USA.
Nicholas L
NL
Bayless
Department of Developmental Biology, Stanford School of Medicine, Stanford University, Stanford, CA 94305, USA.
Rachel S
RS
Greenberg
Department of Developmental Biology, Stanford School of Medicine, Stanford University, Stanford, CA 94305, USA; Department of Chemical and Systems Biology, Stanford School of Medicine, Stanford University, Stanford, CA 94305, USA.
Tomek
T
Swigut
Department of Developmental Biology, Stanford School of Medicine, Stanford University, Stanford, CA 94305, USA; Department of Chemical and Systems Biology, Stanford School of Medicine, Stanford University, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford School of Medicine, Stanford University, Stanford, CA 94305, USA; Institute of Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford University, Stanford, CA 94305, USA. Electronic address: wysocka@stanford.edu.
Joanna
J
Wysocka
Stanford Immunology, Stanford School of Medicine, Stanford University, Stanford, CA 94305, USA; Department of Medicine, Stanford School of Medicine, Stanford University, Stanford, CA 94305, USA. Electronic address: cblish@stanford.edu.
Catherine A
CA
Blish
D017209:Apoptosis; D001921:Brain / Q000196:embryology; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D003716:Dengue Virus / Q000254:growth & development; D006801:Humans; D008954:Models, Biological; D009432:Neural Crest / Q000378:metabolism* / Q000821:virology*; D055495:Neurogenesis / Q000187:drug effects*; D000071244:Zika Virus / Q000254:growth & development*
D016207:Cytokines
Zika virus; cytokines; growth factors; microcephaly; neural development; stem cells
Curr Top Dev Biol. 2015;115:299-320
26589930
Cell Stem Cell. 2016 May 5;18(5):591-6
27038591
N Engl J Med. 2016 Dec 15;375(24):2321-2334
26943629
Science. 2016 May 13;352(6287):816-8
27064148
J Virol. 2015 Sep;89(17 ):8880-96
26085147
Cell Rep. 2016 Jun 28;16(1):232-46
27342126
Nature. 2010 Feb 18;463(7283):958-62
20130577
Cell Host Microbe. 2016 May 11;19(5):720-30
27066744
Brain Res Rev. 2007 Oct;55(2):237-47
17765317
J Neurosci. 2006 Nov 15;26(46):12089-99
17108182
J Am Soc Hypertens. 2015 Dec;9(12 ):975-84.e3
26565110
Endocrinology. 2010 Apr;151(4):1853-62
20160138
Cell. 2015 Sep 24;163(1):68-83
26365491
Nature. 2011 Feb 10;470(7333):279-83
21160473
Cell Stem Cell. 2016 May 5;18(5):587-90
26952870
Development. 2012 Apr;139(8):1371-80
22434866
BMJ. 2016 Apr 13;353:i1901
27075009
FEMS Microbiol Rev. 2015 Mar;39(2):155-70
25725010
Cell Stem Cell. 2012 Nov 2;11(5):633-48
22981823