Decidual NK cells kill Zika virus–infected trophoblasts
Sumit Sen Santara, Ângela C. Crespo, Sachin Mulik, Cristian Ovies, Selma Boulenouar, Jack L. Strominger, Judy Lieberman
Abstract
Significance Natural killer cells (NK) defend against viruses. Decidual NK (dNK), which comprise ∼70% of decidual leukocytes during early pregnancy, are poorly cytotoxic but promote placentation. Zika virus (ZIKV) can cause fetal loss and birth defects. A strong dNK-mediated antiviral defense could provide a barrier to placental infections. Here, we show that ZIKV infection transforms immune-tolerated trophoblasts into dNK targets because ZIKV replicates in the endoplasmic reticulum (ER) and causes ER stress, which triggers NK killing. Unlike in the case of other viral infections, dNK release their granules and kill ZIKV-infected trophoblasts. In a trophoblast-like cell line, human primary extravillous trophoblasts, 3D villous explants, and Ifnar1 −/− pregnant mice, dNK reduce placental and fetal viral loads and protect against fetal loss.