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Zika virus infection induces endoplasmic reticulum stress and apoptosis in placental trophoblasts
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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838309/ https://www.ncbi.nlm.nih.gov/pubmed/33500388 http://dx.doi.org/10.1038/s41420-020-00379-8 |
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author | Muthuraj, Philma Glora Sahoo, Prakash K. Kraus, Madison Bruett, Taylor Annamalai, Arun S. Pattnaik, Aryamav Pattnaik, Asit K. Byrareddy, Siddappa N. Natarajan, Sathish Kumar |
author_facet | Muthuraj, Philma Glora Sahoo, Prakash K. Kraus, Madison Bruett, Taylor Annamalai, Arun S. Pattnaik, Aryamav Pattnaik, Asit K. Byrareddy, Siddappa N. Natarajan, Sathish Kumar |
author_sort | Muthuraj, Philma Glora |
collection | PubMed |
description | 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 1α (P-IRE1α), and its downstream target, the spliced form of XBP1 mRNA, phosphorylated eukaryotic initiation factor 2α (P-eIF2α), and activation of cJun N-terminal Kinase (JNK) and p38 mitogen activated protein kinase (MAPK) after 16–24 h 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. |
format | Online Article Text |
id | pubmed-7838309 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-78383092021-01-29 Zika virus infection induces endoplasmic reticulum stress and apoptosis in placental trophoblasts Muthuraj, Philma Glora Sahoo, Prakash K. Kraus, Madison Bruett, Taylor Annamalai, Arun S. Pattnaik, Aryamav Pattnaik, Asit K. Byrareddy, Siddappa N. Natarajan, Sathish Kumar Cell Death Discov Article 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 1α (P-IRE1α), and its downstream target, the spliced form of XBP1 mRNA, phosphorylated eukaryotic initiation factor 2α (P-eIF2α), and activation of cJun N-terminal Kinase (JNK) and p38 mitogen activated protein kinase (MAPK) after 16–24 h 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. Nature Publishing Group UK 2021-01-26 /pmc/articles/PMC7838309/ /pubmed/33500388 http://dx.doi.org/10.1038/s41420-020-00379-8 Text en © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Muthuraj, Philma Glora Sahoo, Prakash K. Kraus, Madison Bruett, Taylor Annamalai, Arun S. Pattnaik, Aryamav Pattnaik, Asit K. Byrareddy, Siddappa N. Natarajan, Sathish Kumar Zika virus infection induces endoplasmic reticulum stress and apoptosis in placental trophoblasts |
title | Zika virus infection induces endoplasmic reticulum stress and apoptosis in placental trophoblasts |
title_full | Zika virus infection induces endoplasmic reticulum stress and apoptosis in placental trophoblasts |
title_fullStr | Zika virus infection induces endoplasmic reticulum stress and apoptosis in placental trophoblasts |
title_full_unstemmed | Zika virus infection induces endoplasmic reticulum stress and apoptosis in placental trophoblasts |
title_short | Zika virus infection induces endoplasmic reticulum stress and apoptosis in placental trophoblasts |
title_sort | zika virus infection induces endoplasmic reticulum stress and apoptosis in placental trophoblasts |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838309/ https://www.ncbi.nlm.nih.gov/pubmed/33500388 http://dx.doi.org/10.1038/s41420-020-00379-8 |
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