title: Zika Virus Infects Early- and Midgestation Human Maternal Decidual Tissues, Inducing Distinct Innate Tissue Responses in the Maternal-Fetal Interface.
abstract: 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 cell-free 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.
  
  
  
  In view of the rapid spread of the current ZIKV epidemic and the severe manifestations of congenital ZIKV infection, it is crucial to learn the fundamental mechanisms of viral transmission from the mother to the fetus. Our studies of ZIKV infection in the authentic tissues of the human maternal-fetal interface unveil a route of transmission whereby virus originating from the mother could reach the fetal compartment via efficient replication within the maternal decidual aspect of the placenta, coinhabited by maternal and fetal cells. The identified distinct placental tissue innate immune responses and damage pathways could provide a mechanistic basis for some of the placental developmental abnormalities associated with ZIKV infection. The findings in the unique model of the human decidua should pave the way to future studies examining the interaction of ZIKV with decidual immune cells and to evaluation of therapeutic interventions aimed at the earliest stages of transmission.
authors.affiliation: Clinical Virology Unit, Hadassah Hebrew University Medical Center, Jerusalem, Israel.|Department of Biochemistry and the Chanock Center for Virology, IMRIC, The Hebrew University Faculty of Medicine, Jerusalem, Israel.
authors.forename: Yiska
authors.initials: Y
authors.lastname: Weisblum
authors.affiliation: Clinical Virology Unit, Hadassah Hebrew University Medical Center, Jerusalem, Israel.|Department of Biochemistry and the Chanock Center for Virology, IMRIC, The Hebrew University Faculty of Medicine, Jerusalem, Israel.
authors.forename: Esther
authors.initials: E
authors.lastname: Oiknine-Djian
authors.affiliation: Clinical Virology Unit, Hadassah Hebrew University Medical Center, Jerusalem, Israel.|Department of Biochemistry and the Chanock Center for Virology, IMRIC, The Hebrew University Faculty of Medicine, Jerusalem, Israel.
authors.forename: Olesya M
authors.initials: OM
authors.lastname: Vorontsov
authors.affiliation: Department of Obstetrics and Gynecology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Ronit
authors.initials: R
authors.lastname: Haimov-Kochman
authors.affiliation: Department of Biochemistry and the Chanock Center for Virology, IMRIC, The Hebrew University Faculty of Medicine, Jerusalem, Israel.
authors.forename: Zichria
authors.initials: Z
authors.lastname: Zakay-Rones
authors.affiliation: Department of Pathology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Karen
authors.initials: K
authors.lastname: Meir
authors.affiliation: Department of Obstetrics and Gynecology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Shveiky
authors.affiliation: Bioinformatics Unit of the I-CORE Computation Center, The Hebrew University and Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Sharona
authors.initials: S
authors.lastname: Elgavish
authors.affiliation: Bioinformatics Unit of the I-CORE Computation Center, The Hebrew University and Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Nevo
authors.affiliation: Bioinformatics Unit of the I-CORE Computation Center, The Hebrew University and Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Moshe
authors.initials: M
authors.lastname: Roseman
authors.affiliation: Center for Genomic Technologies, Alexander Silberman Institute of Life Sciences, Hebrew University, Jerusalem, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Bronstein
authors.affiliation: Department of Obstetrics and Gynecology, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Stockheim
authors.affiliation: Clinical Virology Unit, Hadassah Hebrew University Medical Center, Jerusalem, Israel.|Department of Biochemistry and the Chanock Center for Virology, IMRIC, The Hebrew University Faculty of Medicine, Jerusalem, Israel.
authors.forename: Ido
authors.initials: I
authors.lastname: From
authors.affiliation: Department of Obstetrics and Gynecology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Iris
authors.initials: I
authors.lastname: Eisenberg
authors.affiliation: Department of Obstetrics and Gynecology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Aya A
authors.initials: AA
authors.lastname: Lewkowicz
authors.affiliation: Department of Obstetrics and Gynecology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Simcha
authors.initials: S
authors.lastname: Yagel
authors.affiliation: Department of Biochemistry and the Chanock Center for Virology, IMRIC, The Hebrew University Faculty of Medicine, Jerusalem, Israel.
authors.forename: Amos
authors.initials: A
authors.lastname: Panet
authors.affiliation: Clinical Virology Unit, Hadassah Hebrew University Medical Center, Jerusalem, Israel dana.wolf@ekmd.huji.ac.il.
authors.forename: Dana G
authors.initials: DG
authors.lastname: Wolf
mesh_terms: D000818:Animals; D002460:Cell Line; D002824:Chorionic Villi / Q000821:virology; D003587:Cytomegalovirus / Q000276:immunology; D003586:Cytomegalovirus Infections / Q000276:immunology / Q000635:transmission / Q000821:virology; D003656:Decidua / Q000821:virology*; D004198:Disease Susceptibility; D005260:Female; D015870:Gene Expression; D005865:Gestational Age; D006801:Humans; D007113:Immunity, Innate; D018445:Infectious Disease Transmission, Vertical; D007372:Interferons / Q000235:genetics / Q000378:metabolism; D010920:Placenta / Q000821:virology*; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D015398:Signal Transduction; D000071244:Zika Virus / Q000502:physiology*; D000071243:Zika Virus Infection / Q000276:immunology* / Q000378:metabolism / Q000635:transmission / Q000821:virology*
chemical_list: D007372:Interferons
keywords: congenital HCMV; congenital Zika virus; decidua; decidual innate immune response; intrauterine transmission; organ culture; placenta