TY - JOUR
T1 - Zika Virus Infection during Pregnancy in Mice Causes Placental Damage and Fetal Demise
AU - Miner, Jonathan J.
AU - Cao, Bin
AU - Govero, Jennifer
AU - Smith, Amber M.
AU - Fernandez, Estefania
AU - Cabrera, Omar H.
AU - Garber, Charise
AU - Noll, Michelle
AU - Klein, Robyn S.
AU - Noguchi, Kevin K.
AU - Mysorekar, Indira U.
AU - Diamond, Michael S.
N1 - Funding Information:
This work was supported by grants from the NIH (R01 AI073755 and R01 AI104972 to M.S.D., R01 HD052664 to K.K.N., and R01 NS052632 to R.S.K.) and the Intellectual and Developmental Disabilities Research Center at Washington University (NIH/NICHD U54 HD087011). J.J.M., E.F., and D.J.P. were supported by a Rheumatology Research Foundation Scientist Development Award, NIH Pre-doctoral training grant award (T32 AI007163), and the NIH Research Education Program (R25 HG006687), respectively. The work also was supported by a Preventing Prematurity Initiative grant from the Burroughs Wellcome Fund and a Prematurity Research Initiative Investigator award from the March of Dimes (to I.U.M). We thank Wandy Betty for her TEM assistance, Fredrik Kraus for his expertise in placental pathology, and Justin Richner for advice with establishing the RNA FISH assays. Finally, we acknowledge Xavier de Lamballerie (Emergence des Pathologies Virales, Aix-Marseille Université, Marseille, France) and the European Virus Archive goes Global (EVAg) for consenting to the use of H/PF/2013 ZIKV strain for this study under a material transfer agreement with the EVAg parter, Aix-Marseille Université. M.S.D. is a consultant for Inbios, Visterra, and Takeda Pharmaceuticals and on the Scientific Advisory Boards of Moderna and OraGene.
Funding Information:
NIH (R01 AI073755 and R01 AI104972 to M.S.D., R01 HD052664 to K.K.N., and R01 NS052632
Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/5/19
Y1 - 2016/5/19
N2 - Zika virus (ZIKV) infection in pregnant women causes intrauterine growth restriction, spontaneous abortion, and microcephaly. Here, we describe two mouse models of placental and fetal disease associated with in utero transmission of ZIKV. Female mice lacking type I interferon signaling (Ifnar1-/-) crossed to wild-type (WT) males produced heterozygous fetuses resembling the immune status of human fetuses. Maternal inoculation at embryonic day 6.5 (E6.5) or E7.5 resulted in fetal demise that was associated with ZIKV infection of the placenta and fetal brain. We identified ZIKV within trophoblasts of the maternal and fetal placenta, consistent with a trans-placental infection route. Antibody blockade of Ifnar1 signaling in WT pregnant mice enhanced ZIKV trans-placental infection although it did not result in fetal death. These models will facilitate the study of ZIKV pathogenesis, in utero transmission, and testing of therapies and vaccines to prevent congenital malformations.
AB - Zika virus (ZIKV) infection in pregnant women causes intrauterine growth restriction, spontaneous abortion, and microcephaly. Here, we describe two mouse models of placental and fetal disease associated with in utero transmission of ZIKV. Female mice lacking type I interferon signaling (Ifnar1-/-) crossed to wild-type (WT) males produced heterozygous fetuses resembling the immune status of human fetuses. Maternal inoculation at embryonic day 6.5 (E6.5) or E7.5 resulted in fetal demise that was associated with ZIKV infection of the placenta and fetal brain. We identified ZIKV within trophoblasts of the maternal and fetal placenta, consistent with a trans-placental infection route. Antibody blockade of Ifnar1 signaling in WT pregnant mice enhanced ZIKV trans-placental infection although it did not result in fetal death. These models will facilitate the study of ZIKV pathogenesis, in utero transmission, and testing of therapies and vaccines to prevent congenital malformations.
UR - http://www.scopus.com/inward/record.url?scp=84969960228&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2016.05.008
DO - 10.1016/j.cell.2016.05.008
M3 - Article
C2 - 27180225
AN - SCOPUS:84969960228
SN - 0092-8674
VL - 165
SP - 1081
EP - 1091
JO - Cell
JF - Cell
IS - 5
ER -