Constitutive expression and distinct properties of IFN-epsilon protect the female reproductive tract from Zika virus infection.
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE223635 | GEO | 2023/02/14
REPOSITORIES: GEO
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Project description:Interferon ε (IFNε), a unique type I IFN, is thought to protect the host against sexually transmitted infections. Unlike conventional type I IFNs (e.g., IFNα/β), whose expression is undetectable at baseline, IFNε expression is detectable in the epithelium of mucosal tissues, particularly the female reproductive tract (FRT). We found that IFNε expression was not limited to epithelial cells at the FRT. Importantly, in contrast to previous reports, IFNε expression in plasmacytoid dendritic cells and primary cervical epithelial cells was induced by viral infection and by activation of TLR3 or 4 in PBMCs. Induction of IFNε mRNAs was also found in cervicovaginal tissues (CVT) of Zika virus (ZIKV)-infected mice. Mice with IFNε deficiency (Ifnε-/-) did not have impaired induction of interferon-stimulated genes except IFNl, but had altered epithelial and collagen structure in the CVT. Ifnε-/- mice exhibited increased susceptibility to ZIKV infection via an intravaginal route but not via a subcutaneous route, indicating that the protective effect of IFNe was specific to the FRT. Infected Ifnε-/- mice had higher and more sustained viral loads than infected wild-type (WT) mice. Detection of ZIKV infection by single molecule in situ hybridization confirmed that virus spread faster in Ifnε-/- mice than in WT mice. Recombinant murine IFNε protected Ifnar1-/- mice against ZIKV infection when administered through an intravaginal route but not when administered through a subcutaneous route, indicating that the specific role of IFNe at the FRT is independent of IFNAR1 signaling. Our findings indicate that IFNε mediates a novel FRT-specific protective effect on mucosal immunity that limits Zika virus spread.
2023-05-11 | GSE228359 | GEO
Project description:Background: The developing field of osteoimmunology supports importance of an interferon(IFN) response pathway in osteoblasts. Clarifying osteoblast-IFN interactions is important because IFN is used as salvage anti-tumor therapy but systemic toxicity is high with variable clinical results. In addition, osteoblast response to systemic bursts and disruptions of IFN pathways induced by viral infection may influence bone remodeling. ZIKA virus(ZIKV) infection impacts bone development in humans and IFN response in vitro. Consistently, initial evidence of permissivity to ZIKV has been reported in human osteoblasts. Hypothesis: Osteoblast-like Saos-2 cells are permissive to ZIKV and responsive to IFN. Methods: Multiple approaches were used to assess whether Saos-2 cells are permissive to ZIKV infection and exhibit IFN-mediated ZIKV suppression. Proteomic methods were used to evaluate impact of ZIKV and IFN on Saos-2 cells. Results: Evidence is presented confirming Saos-2 cells are permissive to ZIKV and support IFN-mediated suppression of ZIKV. ZIKV and IFN differentially impact the Saos-2 proteome. Both ZIKV and IFN suppress proteins associated with microcephaly/pseudo-TORCH syndrome (BI1, KIF20 and UBP18), and ZIKV induces potential entry factor PLVAP. Conclusions: Transient ZIKV infection influences osteoimmune state, and IFN and ZIKV activate distinct proteomes in Saos-2 cells, which could inform therapeutic, engineered, disruptions.
2020-11-03 | PXD016398 | Pride
Project description:The role of the human type I interferon (IFN-I) system in restricting Zika virus (ZIKV) is uncertain. Here, genetic and pharmacological ablation of IFN-I signalling enhanced ZIKV replication and cytopathicity in macrophages and microglia, key cells in ZIKV transmission and pathogenesis. Thus, despite the extensive IFN-I countermeasures employed by ZIKV, IFN-I dictates the outcome of infection in macrophages. Therapeutic manipulation of the IFN-I system may bring clinical benefit in ZIKV.
2022-10-31 | GSE198542 | GEO
Project description:The emerging threat to global health associated with the Zika virus (ZIKV) epidemics and its link to severe complications highlights a growing need to better understand the pathogenic mechanisms of ZIKV. Accumulating evidence for a critical role of type I interferon (IFN-I) in protecting hosts from ZIKV infection lies in the findings that ZIKV has evolved various strategies to subvert the host defense line by counteracting the early IFN induction or subsequent IFN signaling. Yet, mechanisms underlying the counter-IFN capability of ZIKV and its proteins, which might contribute to the well-recognized broad cellular tropisms and persistence of ZIKV, remain to be fully understood. In our current study, using RNA sequencing-based transcriptional profiling from the whole blood cells isolated from patients acutely infected by ZIKV, we found that transcriptional signatures of antiviral interferon-stimulated genes and innate immune sensors was absent in ZIKV-infected patients presents inactive as compared to healthy donors, suggesting that ZIKV might suppress the induction of IFN-I during the natural infection process in human. Furthermore, utilizing cellular or extracellular analysis of molecular interaction in a ZIKV NS4A-overexpression system, or in the context of actual ZIKV infection, we have identified that ZIKV NS4A directly binds MAVS and thereby interrupts RIG-I/MAVS interaction through its CARD-TM domains, leading to attenuated production of IFN-I. Taken together, these findings originated from patient studies have added new knowledge and molecular details to our understanding regarding how ZIKV mediates suppression of the IFN-I system and may provide new basis for future development of anti-ZIKV strategies.
2019-06-16 | GSE123835 | GEO
Project description:Administration of recombinant interferons to 3D brain organoid cultures infected with ZIKV identifies IFN-beta as compound that alleviates organoid damage and inhibits ZIKV
2021-04-09 | GSE123816 | GEO
Project description:Zika virus (ZIKV) is a mosquito-transmitted positive-sense RNA virus in the family Flaviviridae. ZIKV infections are associated with neurodevelopmental deficiencies termed Congenital Zika Syndrome. ZIKV strains are grouped into three phylogenetic lineages: East African, West African, and Asian, which contains the American lineage. RNA virus genomes exist as genetically-related sequences. The heterogeneity of these viral populations is implicated in viral fitness, and genome diversity is correlated to virulence. This study examines genetic diversity of representative ZIKV strains from all lineages utilizing next generation sequencing (NGS). Inter-lineage diversity results indicate that ZIKV lineages differ broadly from each other; however, intra-lineage comparisons of American ZIKV strains isolated from human serum or placenta show differences in diversity when compared to ZIKVs from Asia and West Africa. This study describes the first comprehensive NGS analysis of all ZIKV lineages and posits that sub-consensus-level diversity may provide a framework for understanding ZIKV fitness during infection.
2018-12-31 | E-MTAB-5945 | biostudies-arrayexpress
Project description:Virus infection induces the production of type I and type II interferons (IFN-I and IFN-II), cytokines that mediate the antiviral response. IFN-I (IFN-a and -b) induces the assembly of ISGF3 (interferon-stimulated gene factor 3), a multimeric transcriptional activation complex comprised of STAT1, STAT2 and IRF9. IFN-II (IFN-g) induces the homodimerization of STAT1 to form the GAF (gamma-activated factor) complex. ISGF3 and GAF bind specifically to distinct regulatory DNA sequences located upstream of IFN-I and II inducible genes, respectively, and activate the expression of distinct set of antiviral genes. The balance between the type I and type II IFN pathways plays a critical role in orchestrating the innate and adaptive immune systems. Here, we show that the phosphorylation of STAT1 by IKKε (IkB-related kinase epsilon) inhibits STAT1 homodimerization, and thus GAF formation, but does not disrupt ISGF3 formation. Therefore, virus and/or IFN-I activation of IKKε suppresses GAF-dependent transcription and promotes ISGF3-dependent transcription. In the absence of IKKε, GAF-dependent transcription is enhanced at the expense of ISGF3-mediated transcription, rendering cells less resistant to infection. We conclude that IKKε plays a critical role in regulating the balance between the IFN-I and IFN-II signaling pathways. ChIP-seq libraries were constructed with an antibody targeting STAT1 from bone marrow macrophages treated with interferon
2011-12-01 | E-GEOD-33913 | biostudies-arrayexpress
Project description:Zika virus (ZIKV) infection during pregnancy results in an increased risk of spontaneous abortion and vertical transmission across placenta results in severe congenital defects in newborns. While the infectivity and pathological effects of ZIKV on the placental trophoblast progenitor cells in early human embryos remains largely unknown. Here, using the human trophoblast stem cells (hTSCs) isolated from human blastocyst, we showed that hTSCs were permissive to ZIKV infection, while resistance to ZIKV increased with differentiation. Combined CRISPR/Cas9-mediated gene knockout and RNA-seq assays, we demonstrated that the intrinsic expression of AXL and TIM-1, as well as the absence of potent interferon (IFN)-stimulated genes (ISGs), contributed to the high sensitivity of hTSCs to ZIKV. Furthermore, using our newly developed hTSC-derived 3 dimensional (3D) placental trophoblast organoid model, we demonstrated that ZIKV infection completely disrupted the structure of mature hTSC-organoids and inhibited syncytialization. Overall, our results clearly demonstrated that hTSCs represented the major target cells of ZIKV, and a possible reduced syncytialization may result from ZIKV infection of early developing placenta. These findings deepened our understanding of the characteristics and consequences of ZIKV infection of trophoblast stem cells in early human embryo.
2023-08-03 | GSE229702 | GEO
Project description:Zika virus (ZIKV) is a mosquito-borne flavivirus that caused an epidemic in the Americas in 2016 and is linked to severe neonatal birth defects, including microcephaly and spontaneous abortion. To better understand the host response to ZIKV infection, we adapted the 10x Genomics Chromium single cell RNA sequencing (scRNA-seq) assay to simultaneously capture viral RNA and host mRNA. Using this assay, we profiled the antiviral landscape in a population of human moDCs infected with ZIKV at the single cell level. The bystander cells, which lacked detectable viral RNA, expressed an antiviral state that was enriched for genes coinciding predominantly with a type I interferon (IFN) response. Within the infected cells, viral RNA negatively correlated with type I IFN dependent and independent genes (antiviral module). We modeled the ZIKV specific antiviral state at the protein level leveraging experimentally derived protein-interaction data. We identified a highly interconnected network between the antiviral module and other host proteins. In this work, we propose a new paradigm for the antiviral response to a specific virus, combining an unbiased list of genes that highly correlate with viral RNA on a per cell basis with experimental protein interaction data. Our ZIKV-inclusive scRNA-seq assay will serve as a useful tool to gaining greater insight into the host response to ZIKV and can be applied more broadly to the flavivirus field.
2024-03-20 | GSE230571 | GEO
Project description:Zika virus (ZIKV) is a mosquito-transmitted positive-sense RNA virus in the family Flaviviridae. Candidate live-attenuated vaccine (LAV) viruses with engineered deletions in the 3’UTR provide immunity and protection in animal models of ZIKV infection, and phenotypic studies show that LAVs retain protective abilities following in vitro passage. The present study investigates the genetic diversity of wild-type (WT) parent ZIKV and its candidate LAVs using next generation sequencing analysis of five sequential in vitro passages. ZIKV RNA from was transfected into Vero cells, incubated for nine days, harvested, and clarified by centrifugation to generate passage 0 (P0) ZIKV infectious clones. Subsequently, P0 ZIKVs were blind-passaged into fresh cultures to generate P1, then serially through P5. P1-P5 stocks were harvested from cell media at 4-5 days post-infection. ZIKV RNA from 3’UTR deletion mutants were transfected into Vero cells, incubated for nine days, harvested, and clarified by centrifugation to generate passage 0 (P0) ZIKV infectious clones. Subsequently, P0 ZIKVs were blind-passaged into fresh cultures to generate P1, then serially through P5. P1-P5 stocks were harvested from cell media at 4-5 days post-infection. Genetic diversity of the viruses were assessed by evaluating both the variability (or uncertainty) at each nucleotide position was determined using Shannon entropy calculations and identified single nucleotide variants (SNVs). The results showed both the parental WT and LAV derivatives increase in genetic diversity with evidence of adaptation following passage.
2020-04-13 | E-MTAB-8905 | biostudies-arrayexpress