Stress-induced unfolded protein response contributes to Zika virus–associated microcephaly

Gladwyn-Ng, Ivan; Cordón-Barris, Lluís; Alfano, Christian; Creppe, Catherine; Couderc, Thérèse; Morelli, Gabriele; Thelen, Nicolas; America, Michelle; Bessières, Bettina; Encha‐Razavi, Férechté; Bonnière, Maryse; Suzuki, Ikuo; Flamand, Marie; Vanderhaeghen, Pierre; Thiry, Marc; Lecuit, Marc; Nguyen, Laurent

doi:10.1038/s41593-017-0038-4

Cited by 112 publications

(145 citation statements)

References 40 publications

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“…Accordingly, a therapeutic application for these Hsp70 inhibitors could involve protection from ZIKV infection to trophoblast cells, which form the outer layer of a blastocyst and develop into a large part of the placenta, as well as to neural stem cells that will develop into neuronal lineages. The human trophoblast cell line JEG3 and human neural stem cells (hNSCs) derived from H9 (WA09) embryonic stem cells have been used as relevant models for ZIKV infection of trophoblast (Miner et al, 2016; Tabata et al, 2016) and fetal NSCs (Gladwyn-Ng et al, 2018), respectively. As JG40 and JG345 were toxic to these cells at higher concentrations (5 μM; Figure S6A), we restricted the treatment level to 1.65 μM, where toxicity was reduced (>80% survival).…”

Section: Resultsmentioning

confidence: 99%

Zika Virus Dependence on Host Hsp70 Provides a Protective Strategy against Infection and Disease

et al. 2019

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SUMMARY The spread of mosquito-borne Zika virus (ZIKV), which causes neurological disorders and micro-cephaly, highlights the need for countermeasures against sudden viral epidemics. Here, we tested the concept that drugs targeting host proteostasis pro-vide effective antivirals. We show that different cyto-solic Hsp70 isoforms are recruited to ZIKV-induced compartments and are required for virus replication at pre- and post-entry steps. Drugs targeting Hsp70 significantly reduce replication of different ZIKV strains in human and mosquito cells, including hu-man neural stem cells and a placental trophoblast cell line, at doses without appreciable toxicity to the host cell. By targeting several ZIKV functions, including entry, establishment of active replication complexes, and capsid assembly, Hsp70 inhibitors are refractory to the emergence of drug-resistant virus. Importantly, these drugs protected mouse models from ZIKV infection, reducing viremia, mor-tality, and disease symptoms. Hsp70 inhibitors are thus attractive candidates for ZIKV therapeutics with the added benefit of a broad spectrum of action.

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Section: Resultsmentioning

confidence: 99%

Zika Virus Dependence on Host Hsp70 Provides a Protective Strategy against Infection and Disease

et al. 2019

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“…2) [47]. Additional evidence of ER stress and UPR activation are demonstrated in the elevated expression of GRP78 and other chaperones such as calnexin, calreticulin, and protein disulfide isomerase (PDI) in ZIKV-infected neural cells in vitro and in vivo [35,48,49]. Increased expression of these ER stress markers was accompanied by impaired indirect neurogenesis and microcephalic phenotype in mice [49].…”

Section: Zikv Induces Er Stress and The Unfolded Protein Responsementioning

confidence: 99%

“…Additional evidence of ER stress and UPR activation are demonstrated in the elevated expression of GRP78 and other chaperones such as calnexin, calreticulin, and protein disulfide isomerase (PDI) in ZIKV-infected neural cells in vitro and in vivo [35,48,49]. Increased expression of these ER stress markers was accompanied by impaired indirect neurogenesis and microcephalic phenotype in mice [49]. This finding is consistent with a previous report wherein the induction of UPR in cerebral apical progenitor cells tipped neuronal differentiation towards direct neurogenesis at the expense of indirect neurogenesis, leading to depleted intermediate progenitors, reduced overall cortical neuron output, and diminished cerebral volume, which ultimately caused microcephaly in vivo [50].…”

Section: Zikv Induces Er Stress and The Unfolded Protein Responsementioning

confidence: 99%

“…EDEM-1 is an enzyme involved in the ERAD process that recognizes and facilitates retrotranslocation of misfolded proteins to the cytosol for subsequent proteasomal degradation and thus, alleviating stress damage [65]. Instances of aggravated ER stress were also demonstrated in ZIKV-infected cells, which lead to elevated expression of CHOP protein and initiation of ERstress-induced apoptosis [49]. Pharmacological intervention using IRE1 inhibitor, 4μ8C, prevented microcephaly and impaired ZIKV replication in mouse fetal brains [49].…”

Section: Zikv and Ire1mentioning

confidence: 99%

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Endoplasmic reticulum: a focal point of Zika virus infection

et al. 2020

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Zika virus (ZIKV) belongs to the Flavivirus genus of the Flaviviridae family. It is an arbovirus that can cause congenital abnormalities and is sexually transmissible. A series of outbreaks accompanied by unexpected severe clinical complications have captured medical attention to further characterize the clinical features of congenital ZIKV syndrome and its underlying pathophysiological mechanisms. Endoplasmic reticulum (ER) and ER-related proteins are essential in ZIKV genome replication. This review highlights the subcellular localization of ZIKV to the ER and ZIKV modulation on the architecture of the ER. This review also discusses ZIKV interaction with ER proteins such as signal peptidase complex subunit 1 (SPCS1), ER membrane complex (EMC) subunits, and ER translocon for viral replication. Furthermore, the review covers several important resulting effects of ZIKV infection to the ER and cellular processes including ER stress, reticulophagy, and paraptosis-like death. Pharmacological targeting of ZIKVaffected ER-resident proteins and ER-associated components demonstrate promising signs of combating ZIKV infection and rescuing host organisms from severe neurologic sequelae.

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“…He presented evidence that the UPR contributes to neurogenesis and that upregulation of the UPR in neuronal progenitor cells can impact development, resulting in microcephaly in a mouse model. He showed compelling data indicating that ZIKV induces the UPR in neuronal progenitor cells; this was reflected in dysregulated neuronal development and reduced brain mass in ZIKV-infected fetal mice (Gladwyn-Ng et al, 2017). Therapeutic interventions alleviating the UPR reduced the presentation of microcephaly in ZIKV-infected mice, offering the possibility of therapeutic strategies in this area (Gladwyn-Ng et al, 2018).…”

Section: Arbovirusesmentioning

confidence: 99%

2017 international meeting of the Global Virus Network

et al. 2018

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The Global Virus Network (GVN) was established in 2011 to strengthen research and responses to emerging viral causes of human disease and to prepare against new viral pandemics. There are now 40 GVN Centers of Excellence and 6 Affiliate laboratories in 24 countries. The 2017 meeting was held from September 25-27 in Melbourne, Australia, and was hosted by the Peter Doherty Institute for Infection and Immunity and the Institut Pasteur. This report highlights the recent accomplishments of GVN researchers in several important areas of medical virology, including the recent Zika epidemic, infections by human papillomavirus, influenza, HIV, hepatitis C, HTLV-1, and chikungunya viruses, and new and emerging viruses in the Australasia region. Plans for the 2018 meeting also are noted.

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Stress-induced unfolded protein response contributes to Zika virus–associated microcephaly

Cited by 112 publications

References 40 publications

Zika Virus Dependence on Host Hsp70 Provides a Protective Strategy against Infection and Disease

Zika Virus Dependence on Host Hsp70 Provides a Protective Strategy against Infection and Disease

Endoplasmic reticulum: a focal point of Zika virus infection

2017 international meeting of the Global Virus Network

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