Journal
CELL DEATH DISCOVERY
Volume 7, Issue 1, Pages -Publisher
SPRINGERNATURE
DOI: 10.1038/s41420-020-00379-8
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Funding
- Undergraduate Creative Activities & Research Experience (UCARE)
- University of Nebraska-Lincoln
- National Institute of Allergy and Infectious Diseases [R01AI113883]
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ZIKV infection induces apoptosis in placental trophoblasts, possibly through triggering endoplasmic reticulum stress and activating the JNK pathway, while inhibition of JNK significantly prevents ZIKV-induced apoptosis.
Zika virus (ZIKV) infection to a pregnant woman can be vertically transmitted to the fetus via the placenta leading to Congenital Zika syndrome. This is characterized by microcephaly, retinal defects, and intrauterine growth retardation. ZIKV induces placental trophoblast apoptosis leading to severe abnormalities in the growth and development of the fetus. However, the molecular mechanism behind ZIKV-induced apoptosis in placental trophoblasts remains unclear. We hypothesize that ZIKV infection induces endoplasmic reticulum (ER) stress in the trophoblasts, and sustained ER stress results in apoptosis. HTR-8 (HTR-8/SVneo), a human normal immortalized trophoblast cell and human choriocarcinoma-derived cell lines (JEG-3 and JAR) were infected with ZIKV. Biochemical and structural markers of apoptosis like caspase 3/7 activity and percent apoptotic nuclear morphological changes, respectively were assessed. ZIKV infection in placental trophoblasts showed an increase in the levels of CHOP mRNA and protein expression, which is an inducer of apoptosis. Next, we also observed increased levels of ER stress markers such as phosphorylated forms of inositol-requiring transmembrane kinase/endoribonuclease 1 alpha (P-IRE1 alpha), and its downstream target, the spliced form of XBP1 mRNA, phosphorylated eukaryotic initiation factor 2 alpha (P-eIF2 alpha), and activation of cJun N-terminal Kinase (JNK) and p38 mitogen activated protein kinase (MAPK) after 16-24h of ZIKV infection in trophoblasts. Inhibition of JNK or pan-caspases using small molecule inhibitors significantly prevented ZIKV-induced apoptosis in trophoblasts. Further, JNK inhibition also reduced XBP1 mRNA splicing and viral E protein staining in ZIKV infected cells. In conclusion, 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.
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