Zika virus infection induces endoplasmic reticulum stress and apoptosis in placental trophoblasts

Abstract

Zika virus (ZIKV) infection in pregnant woman can be vertically transmitted to the fetus via the placenta leading to Congenital Zika syndrome (CZS). CZS is characterized by microcephaly, retinal defects and intrauterine growth retardation. ZIKV also causes placental pathology leading to severe compromise in the growth and development of the fetus. Further, the molecular mechanism behind ZIKV‐induced apoptosis in placental trophoblasts is unknown. We hypothesize that accumulation of viral proteins in the endoplasmic reticulum could lead to sustained endoplasmic reticulum stress (ER stress) and trigger apoptotic events. Methods HTR‐8, a human normal immortalized trophoblast cell and human choriocarcinoma derived cell lines (JEG‐3 and JAR) were infected with 0.1–1MOI ZIKV. Apoptosis was assessed by characteristic nuclear morphology staining with DAPI and caspase 3/7 activity. Results We observed an increase in the mRNA levels of CHOP and the spliced form of XBP1 gene, 16–24h post infection in trophoblast. We also observed an increase in the levels of ER stress markers such as p‐IRE1α, p‐eif2α, and activation of c‐Jun N‐terminal Kinase (JNK) and p38 mitogen‐activated protein kinase (MAPK) after 16–24h of ZIKV infection in trophoblast. As prolonged ER stress can cause apoptosis, we observed a dramatic increase in trophoblast apoptosis 48h post infection. Mechanistically, inhibition of JNK by SP600125 or pan caspase by Z‐VAD‐FMK significantly blocked ZIKV‐induced apoptosis in trophoblast. In conclusion, the mechanism of ZIKV‐induced placental trophoblast apoptosis involves the activation of ER stress and MAPK activation. Support or Funding Information NIH: P20GM104320, Layman Seed award, UNL, Food for Health Research Initiative, UNL

Saturated free fatty acids induce placental trophoblast lipoapoptosis

“…JEG-3 and JAR cells has similar biochemical and biological characteristics of human term-derived trophoblasts. JAR and HTR-8 cells were cultured in DMEM containing 10% fetal bovine serum, 0.01% plasmocin and JEG-3 cells were cultured in MEM containing 10% fetal bovine serum, and 0.01% plasmocin as described [ 24 ]. All the cells used in the present study were obtained from the American type culture collection (ATCC) and periodically tested for mycoplasma.…”

The Dual Regulation of Apoptosis by Flavivirus

“…Interestingly, ZIKV infection is related to pro-inflammatory cytokine expression and apoptosis in placental explants, thus we propose that human placental explants can be used as a model for studying ZIKV infection in vitro ( Ribeiro et al, 2018 ). Moreover, the mechanism of ZIKV-induced placental trophoblast apoptosis involves the activation of ER stress and JNK activation, and the inhibition of JNK dramatically prevents ZIKV-induced trophoblast apoptosis ( Muthuraj et al, 2021 ).…”