scholarly journals IRE1α Promotes Zika Virus Infection via XBP1

Viruses ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 278 ◽  
Author(s):  
Elena P. Kolpikova ◽  
Ana R. Tronco ◽  
Andreas B. Den Hartigh ◽  
Konner J. Jackson ◽  
Takao Iwawaki ◽  
...  
Keyword(s):  
Er Stress ◽  
Zika Virus ◽  
Cellular Response ◽  
Target Genes ◽  
Transmembrane Protein ◽  
Nuclease Activity ◽  
Congenital Defects ◽  
Zikv Infection ◽  
Response Component ◽  
Xbp1 Mrna

Zika virus (ZIKV) is an emergent member of the Flaviviridae family which causes severe congenital defects and other major sequelae, but the cellular processes that support ZIKV replication are incompletely understood. Related flaviviruses use the endoplasmic reticulum (ER) as a membranous platform for viral replication and induce ER stress during infection. Our data suggest that ZIKV activates IRE1α, a component of the cellular response to ER stress. IRE1α is an ER-resident transmembrane protein that possesses a cytosolic RNase domain. Upon activation, IRE1α initiates nonconventional cytoplasmic splicing of XBP1 mRNA. Spliced XBP1 encodes a transcription factor, which upregulates ER-related targets. We find that ZIKV infection induces XBP1 mRNA splicing and induction of XBP1 target genes. Small molecule inhibitors of IRE1α, including those specific for the nuclease function, prevent ZIKV-induced cytotoxicity, as does genetic disruption of IRE1α. Optimal ZIKV RNA replication requires both IRE1α and XBP1. Spliced XBP1 has been described to cause ER expansion and remodeling and we find that ER redistribution during ZIKV infection requires IRE1α nuclease activity. Finally, we demonstrate that inducible genetic disruption of IRE1α and XBP1 impairs ZIKV replication in a mouse model of infection. Together, our data indicate that the ER stress response component IRE1α promotes ZIKV infection via XBP1 and may represent a potential therapeutic target.

scholarly journals Palmitoleate Protects against Zika Virus-Induced Placental Trophoblast Apoptosis

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 643
Author(s):  
Philma Glora Muthuraj ◽  
Aryamav Pattnaik ◽  
Prakash K. Sahoo ◽  
Md Torikul Islam ◽  
Asit K. Pattnaik ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Er Stress ◽  
Zika Virus ◽  
Intrauterine Growth Restriction ◽  
Maternal Circulation ◽  
Zikv Infection ◽  
Human Trophoblast ◽  
Homologous Protein ◽  
Stress Markers ◽  
Infected Cells

Zika virus (ZIKV) infection in pregnancy is associated with the development of microcephaly, intrauterine growth restriction, and ocular damage in the fetus. ZIKV infection of the placenta plays a crucial role in the vertical transmission from the maternal circulation to the fetus. Our previous study suggested that ZIKV induces endoplasmic reticulum (ER) stress and apoptosis of placental trophoblasts. Here, we showed that palmitoleate, an omega-7 monounsaturated fatty acid, prevents ZIKV-induced ER stress and apoptosis in placental trophoblasts. Human trophoblast cell lines (JEG-3 and JAR) and normal immortalized trophoblasts (HTR-8) were used. We observed that ZIKV infection of the trophoblasts resulted in apoptosis and treatment of palmitoleate to ZIKV-infected cells significantly prevented apoptosis. However, palmitate (saturated fatty acid) did not offer protection from ZIKV-induced ER stress and apoptosis. We also observed that the Zika viral RNA copies were decreased, and the cell viability improved in ZIKV-infected cells treated with palmitoleate as compared to the infected cells without palmitoleate treatment. Further, palmitoleate was shown to protect against ZIKV-induced upregulation of ER stress markers, C/EBP homologous protein and X-box binding protein-1 splicing in placental trophoblasts. In conclusion, our studies suggest that palmitoleate protects placental trophoblasts against ZIKV-induced ER stress and apoptosis.

scholarly journals Zika Virus Infects Human Placental Mast Cells and the HMC-1 Cell Line, and Triggers Degranulation, Cytokine Release and Ultrastructural Changes

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 975 ◽  
Author(s):  
Kíssila Rabelo ◽  
Antônio José da Silva Gonçalves ◽  
Luiz José de Souza ◽  
Anna Paula Sales ◽  
Sheila Maria Barbosa de Lima ◽  
...  
Keyword(s):  
Mast Cells ◽  
Cell Line ◽  
Zika Virus ◽  
Post Infection ◽  
Immune Cell ◽  
Cell Types ◽  
Ultrastructural Changes ◽  
Congenital Defects ◽  
Zikv Infection ◽  
Intracellular Changes

Zika virus (ZIKV) is an emergent arthropod-borne virus whose outbreak in Brazil has brought major public health problems. Infected individuals have different symptoms, including rash and pruritus, which can be relieved by the administration of antiallergics. In the case of pregnant women, ZIKV can cross the placenta and infect the fetus leading to congenital defects. We have identified that mast cells in the placentae of patients who had Zika during pregnancy can be infected. This led to our investigation on the possible role of mast cells during a ZIKV infection, using the HMC-1 cell line. We analyzed their permissiveness to infection, release of mediators and ultrastructural changes. Flow cytometry detection of ZIKV-NS1 expression 24 h post infection in 45.3% of cells showed that HMC-1 cells are permissive to ZIKV infection. Following infection, β-hexosaminidase was measured in the supernatant of the cells with a notable release at 30 min. In addition, an increase in TNF-α, IL-6, IL-10 and VEGF levels were measured at 6 h and 24 h post infection. Lastly, different intracellular changes were observed in an ultrastructural analysis of infected cells. Our findings suggest that mast cells may represent an important source of mediators that can activate other immune cell types during a ZIKV infection, which has the potential to be a major contributor in the spread of the virus in cases of vertical transmission.

scholarly journals Trimester-specific Zika virus infection affects placental responses in women

2019 ◽  
Author(s):  
Fok-Moon Lum ◽  
Vipin Narang ◽  
Susan Hue ◽  
Jie Chen ◽  
Naomi McGovern ◽  
...  
Keyword(s):  
Birth Defects ◽  
Zika Virus ◽  
Cellular Response ◽  
Prenatal Screening ◽  
Acute Infection ◽  
Transcriptomic Analysis ◽  
Placental Development ◽  
Zikv Infection ◽  
Hofbauer Cells ◽  
Screening Procedures

AbstractZika virus (ZIKV) infection during pregnancy is associated with neurologic birth defects, but the effects on placental development are unclear. Full-term placentas from three women, each infected with ZIKV during specific pregnancy trimesters, were harvested for anatomic, immunologic and transcriptomic analysis. In this study, each woman exhibited a unique immune response, but they collectively diverged from healthy controls with raised IL-1RA, IP-10, EGF and RANTES expression, and neutrophil numbers during the acute infection phase. Although ZIKV NS3 antigens co-localized to placental Hofbauer cells, the placentas showed no anatomical defects. Transcriptomic analysis of samples from the placentas revealed that infection during trimester 1 caused a disparate cellular response centered on differential eIF2 signaling, mitochondrial dysfunction and oxidative phosphorylation. These findings should translate to improve clinical prenatal screening procedures for virus-infected pregnant patients.

scholarly journals BBF2H7, a Novel Transmembrane bZIP Transcription Factor, Is a New Type of Endoplasmic Reticulum Stress Transducer

2006 ◽  
Vol 27 (5) ◽  
pp. 1716-1729 ◽  
Author(s):  
Shinichi Kondo ◽  
Atsushi Saito ◽  
Shin-ichiro Hino ◽  
Tomohiko Murakami ◽  
Maiko Ogata ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Transcription Factor ◽  
Er Stress ◽  
Target Genes ◽  
Transmembrane Protein ◽  
Late Phase ◽  
Neuroblastoma Cell ◽  
Bzip Transcription Factor ◽  
Unfolded Proteins

ABSTRACT Endoplasmic reticulum (ER) stress transducers IRE1 (inositol requiring 1), PERK (PKR-like endoplasmic reticulum kinase), and ATF6 (activating transcription factor 6) are well known to transduce signals from the ER to the cytoplasm and nucleus when unfolded proteins accumulate in the ER. Recently, we identified OASIS (old astrocyte specifically induced substance) as a novel ER stress transducer expressed in astrocytes. We report here that BBF2H7 (BBF2 human homolog on chromosome 7), an ER-resident transmembrane protein with the bZIP domain in the cytoplasmic portion and structurally homologous to OASIS, is cleaved at the membrane in response to ER stress. The cleaved fragments of BBF2H7 translocate into the nucleus and can bind directly to cyclic AMP-responsive element sites to activate transcription of target genes. Interestingly, although BBF2H7 protein is not expressed under normal conditions, it is markedly induced at the translational level during ER stress, suggesting that BBF2H7 might contribute to only the late phase of unfolded protein response signaling. In a mouse model of focal brain ischemia, BBF2H7 protein is prominently induced in neurons in the peri-infarction region. Furthermore, in a neuroblastoma cell line, BBF2H7 overexpression suppresses ER stress-induced cell death, while small interfering RNA knockdown of BBF2H7 promotes ER stress-induced cell death. Taken together, our results suggest that BBF2H7 is a novel ER stress transducer and could play important roles in preventing accumulation of unfolded proteins in damaged neurons.

scholarly journals Pregnant Women Infected with Zika Virus Show Higher Viral Load and Immunoregulatory Cytokines Profile with CXCL10 Increase

Viruses ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 80
Author(s):  
Elizabeth Camacho-Zavala ◽  
Clara Santacruz-Tinoco ◽  
Esteban Muñoz ◽  
Rommel Chacón-Salinas ◽  
Ma Isabel Salazar-Sanchez ◽  
...  
Keyword(s):  
Viral Load ◽  
Inflammatory Response ◽  
Pregnant Women ◽  
Inflammatory Cytokines ◽  
Zika Virus ◽  
Epidemiological Surveillance ◽  
Congenital Defects ◽  
Serum Samples ◽  
Zikv Infection ◽  
Anti Inflammatory

Background: Zika virus (ZIKV) infection during pregnancy usually shows only mild symptoms and is frequently subclinical. However, it can be vertically transmitted to the fetus, causing microcephaly and other congenital defects. During pregnancy, the immune environment modifications can alter the response to viruses in general and ZIKV in particular. Objective: To describe the role of pregnancy in the systemic pro- and anti-inflammatory response during symptomatic ZIKV infection. Materials and Methods: A multiplex assay was used to measure 25 cytokines, chemokines, and receptors in 110 serum samples from pregnant and nonpregnant women with and without ZIKV infection with and without symptoms. Samples were collected through an epidemiological surveillance system. Results: Samples from pregnant women with ZIKV infection showed a higher viral load but had similar profiles of inflammatory markers as compared with nonpregnant infected women, except for CXCL10 that was higher in infected pregnant women. Notably, the presence of ZIKV in pregnancy favored a regulatory profile by significantly increasing anti-inflammatory cytokines such as interleukin (IL)-10, receptors IL-1RA, and IL-2R, but only those pro-inflammatory cytokines such as IL-6, interferon (IFN)-α, IFN-γ and IL-17 that are essential for the antiviral response. Interestingly, there were no differences between symptomatic and weakly symptomatic ZIKV-infected groups. Conclusion: Our results revealed a systemic anti-inflammatory cytokine and chemokine profile that could participate in the control of the virus. The anti-inflammatory response in pregnant women infected with ZIKA was characterized by high CXCL10, a cytokine that has been correlated with congenital malformations.

scholarly journals Zika Virus

2020 ◽  
Author(s):  
Marciano Paes ◽  
Kíssila Rabelo
Keyword(s):  
Mast Cells ◽  
Zika Virus ◽  
Post Infection ◽  
Immune Cell ◽  
Cell Types ◽  
Ultrastructural Changes ◽  
Congenital Defects ◽  
Zikv Infection ◽  
Flow Cytometry Detection ◽  
Intracellular Changes

Zika virus (ZIKV) is an emergent arthropod-borne virus whose outbreak in Brazil has brought major public health problems. Infected individuals have different symptoms, including rash and pruritus, which can be relieved by the administration of antiallergics. In the case of pregnant women, ZIKV can cross the placenta and infect the fetus leading to congenital defects. We have identified that mast cells in the placentae of patients who had Zika during pregnancy can be infected. This led to our investigation on the possible role of mast cells during a ZIKV infection, using the HMC-1 cell line. We analyzed their permissiveness to infection, release of mediators and ultrastructural changes. Flow cytometry detection of ZIKV-NS1 expression 24h post infection in 45.3% of cells showed that HMC-1 cells are permissive to ZIKV infection. Following infection, β-hexosaminidase was measured in the supernatant of the cells with a notable release at 30 min. In addition, an increase in TNF-α, IL-6, IL-10 and VEGF levels were measured at 6h and 24h post infection. Lastly, different intracellular changes were observed in an ultrastructural analysis of infected cells. Our findings suggest that mast cells may represent an important source of mediators that can activate other immune cell types during a ZIKV infection, which has the potential to being a major contributor in the spread of the virus in cases of vertical transmission.

Decidual NK cells kill Zika virus–infected trophoblasts

2021 ◽  
Vol 118 (47) ◽  
pp. e2115410118
Author(s):  
Sumit Sen Santara ◽  
Ângela C. Crespo ◽  
Sachin Mulik ◽  
Cristian Ovies ◽  
Selma Boulenouar ◽  
...  
Keyword(s):  
Er Stress ◽  
Natural Killer ◽  
Zika Virus ◽  
First Trimester ◽  
Receptor Ligands ◽  
Zikv Infection ◽  
Pregnant Mice ◽  
Infected Cells ◽  
Spread Of Infection ◽  
Cellular Immune

Zika virus (ZIKV) during pregnancy infects fetal trophoblasts and causes placental damage and birth defects including microcephaly. Little is known about the anti-ZIKV cellular immune response at the maternal–fetal interface. Decidual natural killer cells (dNK), which directly contact fetal trophoblasts, are the dominant maternal immune cells in the first-trimester placenta, when ZIKV infection is most hazardous. Although dNK express all the cytolytic molecules needed to kill, they usually do not kill infected fetal cells but promote placentation. Here, we show that dNK degranulate and kill ZIKV-infected placental trophoblasts. ZIKV infection of trophoblasts causes endoplasmic reticulum (ER) stress, which makes them dNK targets by down-regulating HLA-C/G, natural killer (NK) inhibitory receptor ligands that help maintain tolerance of the semiallogeneic fetus. ER stress also activates the NK activating receptor NKp46. ZIKV infection of Ifnar1−/− pregnant mice results in high viral titers and severe intrauterine growth restriction, which are exacerbated by depletion of NK or CD8 T cells, indicating that killer lymphocytes, on balance, protect the fetus from ZIKV by eliminating infected cells and reducing the spread of infection.

scholarly journals Fibroblast Growth Factor 2 Enhances Zika Virus Infection in Human Fetal Brain

2019 ◽  
Vol 220 (8) ◽  
pp. 1377-1387 ◽  
Author(s):  
Daniel Limonta ◽  
Juan Jovel ◽  
Anil Kumar ◽  
Julia Lu ◽  
Shangmei Hou ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Zika Virus ◽  
Cellular Response ◽  
Fetal Brain ◽  
Fibroblast Growth Factor 2 ◽  
Interferon Response ◽  
Fibroblast Growth ◽  
Human Fetal Brain ◽  
Zikv Infection

Abstract Zika virus (ZIKV) is an emerging pathogen that can cause microcephaly and other neurological defects in developing fetuses. The cellular response to ZIKV in the fetal brain is not well understood. Here, we show that ZIKV infection of human fetal astrocytes (HFAs), the most abundant cell type in the brain, results in elevated expression and secretion of fibroblast growth factor 2 (FGF2). This cytokine was shown to enhance replication and spread of ZIKV in HFAs and human fetal brain explants. The proviral effect of FGF2 is likely mediated in part by suppression of the interferon response, which would represent a novel mechanism by which viruses antagonize host antiviral defenses. We posit that FGF2-enhanced virus replication in the fetal brain contributes to the neurodevelopmental disorders associated with in utero ZIKV infection. As such, targeting FGF2-dependent signaling should be explored further as a strategy to limit replication of ZIKV.

scholarly journals MicroRNAs 145 and 148a Are Upregulated During Congenital Zika Virus Infection

ASN NEURO ◽  
2019 ◽  
Vol 11 ◽  
pp. 175909141985098 ◽  
Author(s):  
Fernanda L. Castro ◽  
Victor E. V. Geddes ◽  
Fábio L. L. Monteiro ◽  
Raphael M. D. T. Gonçalves ◽  
Loraine Campanati ◽  
...  
Keyword(s):  
Zika Virus ◽  
Target Genes ◽  
Neuroblastoma Cell ◽  
In Silico Analysis ◽  
Neuroblastoma Cell Line ◽  
Cellular Migration ◽  
Postmortem Brain ◽  
Zikv Infection ◽  
Cellular Mirnas ◽  
Congenital Zika Syndrome

Zika virus (ZIKV) is an arthropod-borne virus (arbovirus) member of the Flaviviridae family, which has been associated with the development of the congenital Zika syndrome (CZS). RNA viruses, such as flaviviruses, have been reported to exert a profound impact on host microRNAs (miRNAs). Cellular miRNAs modulated by ZIKV may help identify cellular pathways of relevance to pathogenesis. Here, we screened 754 human cellular miRNAs modulated by ZIKV infection (Brazilian PE strain) in a neuroblastoma cell line. Seven miRNAs (miR-99a*, miR-126*, miR-190b, miR-361-3p, miR-522-3p, miR-299-5p, and miR-1267) were downregulated during ZIKV infection, while miR-145 was upregulated. Furthermore, 11 miRNAs were exclusively expressed in ZIKV-infected (miR-148a, miR-342-5p, miR-598, and miR-708-3p) or mock cells (miR-208, miR-329, miR-432-5p, miR-488, miR-518b, miR-520g, and miR-767-5p). Furthermore, in silico analysis indicated that some central nervous system, cellular migration, and adhesion function-related biological processes were overrepresented in the list of target genes of the miRNAs regulated in ZIKV-infected cells, especially for miR-145 and miR-148a. The induction of miR-145 and miR-148a was confirmed in postmortem brain samples from stillborn with severe CZS. Finally, we determined the expression regulation of microcephaly related genes through RNA interference pathway caused by ZIKV directly on neuron cells.

scholarly journals Fragile X mental retardation protein is a Zika virus restriction factor that is antagonized by subgenomic flaviviral RNA

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Ruben Soto-Acosta ◽  
Xuping Xie ◽  
Chao Shan ◽  
Coleman K Baker ◽  
Pei-Yong Shi ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Zika Virus ◽  
Target Genes ◽  
Cultured Cells ◽  
Fragile X ◽  
Restriction Factor ◽  
Zikv Infection ◽  
Viral Genomes ◽  
Fragile X Mental Retardation ◽  
Mental Retardation Protein

Subgenomic flaviviral RNA (sfRNA) accumulates during infection due to incomplete degradation of viral genomes and interacts with cellular proteins to promote infection. Here we identify host proteins that bind the Zika virus (ZIKV) sfRNA. We identified fragile X mental retardation protein (FMRP) as a ZIKV sfRNA-binding protein and confirmed this interaction in cultured cells and mouse testes. Depletion of FMRP elevated viral translation and enhanced ZIKV infection, indicating that FMRP is a ZIKV restriction factor. We further observed that an attenuated ZIKV strain compromised for sfRNA production was disproportionately stimulated by FMRP knockdown, suggesting that ZIKV sfRNA antagonizes FMRP activity. Importantly, ZIKV infection and expression of ZIKV sfRNA upregulated endogenous FMRP target genes in cell culture and ZIKV-infected mice. Together, our observations identify FMRP as a ZIKV restriction factor whose activity is antagonized by the sfRNA. Interaction between ZIKV and FMRP has significant implications for the pathogenesis of ZIKV infections.

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