Paulomi Aldo1, Yuan You1, Klara Szigeti2, Tamas L Horvath1,2, Brett Lindenbach3, Gil Mor4. 1. Division of Reproductive Sciences, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA. 2. Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA. 3. Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA. 4. Division of Reproductive Sciences, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA. gil.mor@yale.edu.
Abstract
PROBLEM: Zika virus (ZIKV) has gained public concern for its association with microcephaly in infants born to ZIKV-infected mothers. To reach the fetus the virus must overcome the defense mechanisms provided by trophoblast cells. Additionally, in the first trimester, the integrity of the placenta is critical for fetal protection as damage to differentiating trophoblast can affect placental formation and function. We sought to investigate the effect of ZIKV infection on trophoblast cells and the factors that might increase the risk for ZIKV infection during pregnancy. METHODS: First-trimester human trophoblast cells, Swan 7.1, were infected with ZIKV, herpes simplex virus-2 (HSV-2), and yellow fiver (YFV). C57BL/6 pregnant mice were infected with HSV-2, ZIKV, or coinfection. Placental viral titers were determined by RT-PCR. RESULTS: ZIKV infection induces apoptosis in first-trimester trophoblasts and prevents differentiation of these cells. Furthermore, HSV-2 infection enhances placental sensitivity to ZIKV by enhancing the expression of TAM receptors, which facilitate ZIKV cell entry. CONCLUSION: These findings may explain the mechanism by which ZIKV breaches the placental barrier to access the fetus. Furthermore, our results suggest that patients with HSV-2 infection are at a higher risk for the teratogenic effects induced by ZIKV.
PROBLEM: Zika virus (ZIKV) has gained public concern for its association with microcephaly in infants born to ZIKV-infected mothers. To reach the fetus the virus must overcome the defense mechanisms provided by trophoblast cells. Additionally, in the first trimester, the integrity of the placenta is critical for fetal protection as damage to differentiating trophoblast can affect placental formation and function. We sought to investigate the effect of ZIKV infection on trophoblast cells and the factors that might increase the risk for ZIKV infection during pregnancy. METHODS: First-trimester human trophoblast cells, Swan 7.1, were infected with ZIKV, herpes simplex virus-2 (HSV-2), and yellow fiver (YFV). C57BL/6 pregnant mice were infected with HSV-2, ZIKV, or coinfection. Placental viral titers were determined by RT-PCR. RESULTS:ZIKV infection induces apoptosis in first-trimester trophoblasts and prevents differentiation of these cells. Furthermore, HSV-2 infection enhances placental sensitivity to ZIKV by enhancing the expression of TAM receptors, which facilitate ZIKV cell entry. CONCLUSION: These findings may explain the mechanism by which ZIKV breaches the placental barrier to access the fetus. Furthermore, our results suggest that patients with HSV-2 infection are at a higher risk for the teratogenic effects induced by ZIKV.
Authors: Sarah N Cross; Julie A Potter; Paulomi Aldo; Ja Young Kwon; Mary Pitruzzello; Mancy Tong; Seth Guller; Carla V Rothlin; Gil Mor; Vikki M Abrahams Journal: J Immunol Date: 2017-09-15 Impact factor: 5.422
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