The recent outbreak of Zika virus (ZIKV) in Brazil has been associated with an increase in microcephaly and adverse pregnancy outcomes. The virus has been isolated from fetal tissues as well as the placenta, however, the effects of ZIKV on early embryonic and placental development is unclear. Moreover, recent reports demonstrate that the virus can be sexually transmitted, which presents a concern for the use of assisted reproductive technologies as it is not known whether the presence of the virus in semen or the follicular fluid poses a risk to embryonic and placental development. Thus, our overall goal is to define the impact of ZIKV on early embryonic development as well as on early placental development. We hypothesize that ZIKV can infect the preimplantation embryo, negatively impact embryonic development, and disrupt trophectodermal differentiation and subsequent placental development. To test this hypothesis, we will conduct the following Specific Aims:
Specific Aim 1. To determine the impact of ZIKV on fertilization, embryo cleavage, blastocyst formation and trophectoderm lineage commitment.
This Aim will test the hypothesis that the presence of ZIKV in seminal plasma or female reproductive tract fluid can affect the earliest stages of embryo development and the trajectory or efficiency of blastocyst formation, and thus determination of placental morphogenesis.
Specific Aim 2. To determine the impact of ZIKV on trophectoderm/embryonic trophoblast differentiated function, gene transcription, and miRNA expression. This experiment will examine potential mechanisms by which embryonic ZIKV infection impacts early placental development and thus the integrity of the maternal- fetal interface. This proposal is directly responsive to a number of the specific areas of high priority listed in PAR-16-106, including the need for ?Studies to understand pregnancy outcomes in women infected with ZIKV?, ?Studies on effects of ZIKV on in vitro fertilization?, ?Studies on whether ZIKV can be transmitted by direct sexual contact or artificial reproductive technology procedures?, and ?Basic research to understand the ZIKV infection pathogenesis and transmission to the fetus?. Utilizing in vitro fertilization and in vitro implantation models, the effect of viral infection on the early embryo and trophoblast lineage can be systematically analyzed. The observations from the proposed research will establish the impact of ZIKV on the developing embryo and placenta, and guide recommendations for use of assisted reproductive technologies and the risk as ZIKV poses to pregnancy and fetal development.

Public Health Relevance

Zika virus can be sexually transmitted and has been associated with the development of fetal and placental abnormalities. Our proposal aims to define the direct effect of Zika virus on the early developing embryo and placental cell lineage at the pre- and periimplantation period. An in vitro fertilization system will be utilized to generate an infection model for early rhesus macaque embryos, in which the growth and function of placental cells near the time of implantation can be monitored to determine the effect of Zika infection on development. Outcomes from this work will address concerns in regards to use of assisted reproductive technologies in light of Zika virus infection.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZHD1)
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Chakhtoura, Nahida Abdo
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University of Wisconsin Madison
Schools of Veterinary Medicine
United States
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Schmidt, Jenna Kropp; Block, Lindsey N; Golos, Thaddeus G (2018) Defining the rhesus macaque placental miRNAome: Conservation of expression of placental miRNA clusters between the macaque and human. Placenta 65:55-64
Rozner, Ann E; Durning, Maureen; Kropp, Jenna et al. (2016) Macrophages modulate the growth and differentiation of rhesus monkey embryonic trophoblasts. Am J Reprod Immunol 76:364-375