Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 214, Issue 8, Pages 2303-2313Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20170957
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Funding
- Preventing Prematurity Initiative grant from Burroughs Wellcome Fund
- Prematurity Research Initiative Investigator award from March of Dimes [21-FY13-28]
- National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development [R01HD091218, R01 AI073755, R01 AI104972]
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Zika virus (ZIKV) infection during pregnancy leads to devastating fetal outcomes, including intrauterine growth restriction and microcephaly. Greater understanding of mechanisms underlying ZIKV maternal-fetal transmission is needed to develop new therapeutic interventions. Here, we define an important role for the autophagy pathway in ZIKV vertical transmission. ZIKV infection induced autophagic activity in human trophoblasts and pharmacological inhibition limited ZIKV infectivity. Furthermore, deficiency in an essential autophagy gene, Atg16l1, in mice limited ZIKV vertical transmission and placental and fetal damage and overall improved placental and fetal outcomes. This protection was due to a placental trophoblast cell-autonomous effect of autophagic activity, not to alterations in systemic maternal ZIKV infection. Finally, an autophagy inhibitor, hydroxychloroquine, approved for use in pregnant women, attenuated placental and fetal ZIKV infection and ameliorated adverse placental and fetal outcomes. Our study reveals new insights into the mechanism of ZIKV vertical transmission and suggests that an autophagy-based therapeutic warrants possible evaluation in humans to diminish the risks of ZIKV maternal-fetal transmission.
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