TY - JOUR
T1 - Peli1 signaling blockade attenuates congenital zika syndrome
AU - Luo, Huanle
AU - Li, Guangyu
AU - Wang, Binbin
AU - Tian, Bing
AU - Gao, Junling
AU - Zou, Jing
AU - Shi, Shuizhen
AU - Zhu, Shuang
AU - Peng, Bi Hung
AU - Adam, Awadalkareem
AU - Martinez, Ariza
AU - Hein, Kimberly
AU - Winkelmann, Evandro R.
AU - Mahmoud, Yoseph
AU - Zhou, Xiaofei
AU - Shan, Chao
AU - Rossi, Shannan
AU - Weaver, Scott
AU - Barrett, Alan D.T.
AU - Sun, Shao Cong
AU - Zhang, Wenbo
AU - Shi, Pei Yong
AU - Wu, Ping
AU - Wang, Tian
N1 - Funding Information:
This work was supported in part by NIH grants R01 AI099123 (T.W.), R01 AI127744 (T. W.), R21 AI140569A1 (T.W.), R21 EY029112 (W. Z. and T.W.), R01 EY022694 and R01 EY026629 (W.Z.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2020 Luo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2020/6
Y1 - 2020/6
N2 - Zika virus (ZIKV) infects pregnant women and causes devastating congenital zika syndrome (CZS). How the virus is vertically transmitted to the fetus and induces neuronal loss remains unclear. We previously reported that Pellino (Peli)1, an E3 ubiquitin ligase, promotes p38MAPK activation in microglia and induction of lethal encephalitis by facilitating the replication of West Nile virus (WNV), a closely related flavivirus. Here, we found that Peli1 expression was induced on ZIKV-infected human monocytic cells, peripheral blood mononuclear cells, human first-trimester placental trophoblasts, and neural stem cell (hNSC)s. Peli1 mediates ZIKV cell attachment, entry and viral translation and its expression is confined to the endoplasmic reticulum. Moreover, Peli1 mediated inflammatory cytokine and chemokine responses and induced cell death in placental trophoblasts and hNSCs. ZIKV-infected pregnant mice lacking Peli1 signaling had reduced placental inflammation and tissue damage, which resulted in attenuated congenital abnormalities. Smaducin-6, a membrane-tethered Smad6-derived peptide, blocked Peli1-mediated NF-κB activation but did not have direct effects on ZIKV infection. Smaducin-6 reduced inflammatory responses and cell death in placental trophoblasts and hNSCs, and diminished placental inflammation and damage, leading to attenuated congenital malformations in mice. Collectively, our results reveal a novel role of Peli1 in flavivirus pathogenesis and suggest that Peli1 promotes ZIKV vertical transmission and neuronal loss by mediating inflammatory cytokine responses and induction of cell death. Our results also identify Smaducin-6 as a potential therapeutic candidate for treatment of CZS.
AB - Zika virus (ZIKV) infects pregnant women and causes devastating congenital zika syndrome (CZS). How the virus is vertically transmitted to the fetus and induces neuronal loss remains unclear. We previously reported that Pellino (Peli)1, an E3 ubiquitin ligase, promotes p38MAPK activation in microglia and induction of lethal encephalitis by facilitating the replication of West Nile virus (WNV), a closely related flavivirus. Here, we found that Peli1 expression was induced on ZIKV-infected human monocytic cells, peripheral blood mononuclear cells, human first-trimester placental trophoblasts, and neural stem cell (hNSC)s. Peli1 mediates ZIKV cell attachment, entry and viral translation and its expression is confined to the endoplasmic reticulum. Moreover, Peli1 mediated inflammatory cytokine and chemokine responses and induced cell death in placental trophoblasts and hNSCs. ZIKV-infected pregnant mice lacking Peli1 signaling had reduced placental inflammation and tissue damage, which resulted in attenuated congenital abnormalities. Smaducin-6, a membrane-tethered Smad6-derived peptide, blocked Peli1-mediated NF-κB activation but did not have direct effects on ZIKV infection. Smaducin-6 reduced inflammatory responses and cell death in placental trophoblasts and hNSCs, and diminished placental inflammation and damage, leading to attenuated congenital malformations in mice. Collectively, our results reveal a novel role of Peli1 in flavivirus pathogenesis and suggest that Peli1 promotes ZIKV vertical transmission and neuronal loss by mediating inflammatory cytokine responses and induction of cell death. Our results also identify Smaducin-6 as a potential therapeutic candidate for treatment of CZS.
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U2 - 10.1371/journal.ppat.1008538
DO - 10.1371/journal.ppat.1008538
M3 - Article
C2 - 32544190
AN - SCOPUS:85086687146
SN - 1553-7366
VL - 16
JO - PLoS Pathogens
JF - PLoS Pathogens
IS - 6
M1 - e1008538
ER -