TY - JOUR
T1 - Zika virus infects early- and midgestation human maternal decidual tissues, inducing distinct innate tissue responses in the maternal-fetal interface
AU - Weisblum, Yiska
AU - Oiknine-Djian, Esther
AU - Vorontsov, Olesya M.
AU - Haimov-Kochman, Ronit
AU - Zakay-Rones, Zichria
AU - Meir, Karen
AU - Shveiky, David
AU - Elgavish, Sharona
AU - Nevo, Yuval
AU - Roseman, Moshe
AU - Bronstein, Michal
AU - Stockheim, David
AU - From, Ido
AU - Eisenberg, Iris
AU - Lewkowicz, Aya A.
AU - Yagel, Simcha
AU - Panet, Amos
AU - Wolf, Dana G.
N1 - Publisher Copyright:
© 2017 American Society for Microbiology.
PY - 2017
Y1 - 2017
N2 - Zika virus (ZIKV) has emerged as a cause of congenital brain anomalies and a range of placenta-related abnormalities, highlighting the need to unveil the modes of maternal-fetal transmission. The most likely route of vertical ZIKV transmission is via the placenta. The earliest events of ZIKV transmission in the maternal decidua, representing the maternal uterine aspect of the chimeric placenta, have remained unexplored. Here, we show that ZIKV replicates in first-trimester human maternal-decidual tissues grown ex vivo as three-dimensional (3D) organ cultures. An efficient viral spread in the decidual tissues was demonstrated by the rapid upsurge and continued increase of tissue-associated ZIKV load and titers of infectious cellfree virus progeny, released from the infected tissues. Notably, maternal decidual tissues obtained at midgestation remained similarly susceptible to ZIKV, whereas fetus-derived chorionic villi demonstrated reduced ZIKV replication with increasing gestational age. A genome-wide transcriptome analysis revealed that ZIKV substantially upregulated the decidual tissue innate immune responses. Further comparison of the innate tissue response patterns following parallel infections with ZIKV and human cytomegalovirus (HCMV) revealed that unlike HCMV, ZIKV did not induce immune cell activation or trafficking responses in the maternal-fetal interface but rather upregulated placental apoptosis and cell death molecular functions. The data identify the maternal uterine aspect of the human placenta as a likely site of ZIKV transmission to the fetus and further reveal distinct patterns of innate tissue responses to ZIKV. Our unique experimental model and findings could further serve to study the initial stages of congenital ZIKV transmission and pathogenesis and evaluate the effect of new therapeutic interventions.
AB - Zika virus (ZIKV) has emerged as a cause of congenital brain anomalies and a range of placenta-related abnormalities, highlighting the need to unveil the modes of maternal-fetal transmission. The most likely route of vertical ZIKV transmission is via the placenta. The earliest events of ZIKV transmission in the maternal decidua, representing the maternal uterine aspect of the chimeric placenta, have remained unexplored. Here, we show that ZIKV replicates in first-trimester human maternal-decidual tissues grown ex vivo as three-dimensional (3D) organ cultures. An efficient viral spread in the decidual tissues was demonstrated by the rapid upsurge and continued increase of tissue-associated ZIKV load and titers of infectious cellfree virus progeny, released from the infected tissues. Notably, maternal decidual tissues obtained at midgestation remained similarly susceptible to ZIKV, whereas fetus-derived chorionic villi demonstrated reduced ZIKV replication with increasing gestational age. A genome-wide transcriptome analysis revealed that ZIKV substantially upregulated the decidual tissue innate immune responses. Further comparison of the innate tissue response patterns following parallel infections with ZIKV and human cytomegalovirus (HCMV) revealed that unlike HCMV, ZIKV did not induce immune cell activation or trafficking responses in the maternal-fetal interface but rather upregulated placental apoptosis and cell death molecular functions. The data identify the maternal uterine aspect of the human placenta as a likely site of ZIKV transmission to the fetus and further reveal distinct patterns of innate tissue responses to ZIKV. Our unique experimental model and findings could further serve to study the initial stages of congenital ZIKV transmission and pathogenesis and evaluate the effect of new therapeutic interventions.
KW - Congenital HCMV
KW - Congenital Zika virus
KW - Decidua
KW - Decidual innate immune response
KW - Intrauterine transmission
KW - Organ culture
KW - Placenta
UR - http://www.scopus.com/inward/record.url?scp=85012024098&partnerID=8YFLogxK
U2 - 10.1128/JVI.01905-16
DO - 10.1128/JVI.01905-16
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C2 - 27974560
AN - SCOPUS:85012024098
SN - 0022-538X
VL - 91
JO - Journal of Virology
JF - Journal of Virology
IS - 4
M1 - e01905-16
ER -