Genome-wide RNA-seq and ATAC-seq analysis of an in vivo human immune response to acute Zika virus infection
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE123541 | GEO | 2018/12/19
REPOSITORIES: GEO
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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.
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Project description:Effects of Zika virus (ZIKV) infection on placental development during pregnancy are unclear. In this study, full-term placentas from three women, each infected with ZIKV during specific pregnancy trimesters, were harvested for anatomic, immunologic and transcriptomic analysis. Each woman exhibited a unique immune response 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 signalling, mitochondrial dysfunction and oxidative phosphorylation. Despite these, the babies were delivered without any congenital anomalies. Nevertheless, these findings should translate to improve clinical prenatal screening procedures for virus-infected pregnant patients.
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Project description:Zika virus (ZIKV) is an emerging, mosquito-borne pathogen associated with a widespread 2015–2016 epidemic in the Western Hemisphere and a proven cause of microcephaly and other fetal brain defects in infants born to infected mothers. ZIKV infections have been also linked to other neurological illnesses in infected adults and children, including Guillain-Barré syndrome (GBS), acute flaccid paralysis (AFP) and meningoencephalitis, but the viral pathophysiology behind those conditions remains poorly understood. Here we investigated ZIKV infectivity in neuroblastoma SH-SY5Y cells, both undifferentiated and following differentiation with retinoic acid. We perform RNA seq, and global trancriptome analysis to corroborate the effect of retinoic acid in SH-SY5Y cells. Then we analyze the virus infection in differentiated and undifferntiated cells. We found that multiple ZIKV strains, representing both the prototype African and contemporary Asian epidemic lineages, were able to replicate in SH-SY5Y cells. Differentiation with resultant expression of mature neuron markers increased infectivity in these cells, and the extent of infectivity correlated with degree of differentiation. Enhanced ZIKV infectivity in a neural cell line following differentiation may contribute to viral neuropathogenesis in the developing or mature central nervous system.
2018-10-20 | GSE121534 | GEO
Project description:Host and genetic viral adaptations enable development of an immunocompetent mouse model of Zika virus infection. This study explored the effect of wildtype Zika virus (ZIKV) and mouse adapted ZIKV infection on the transcriptional profile of mouse adult neuronal stem cells.
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Project description:Ribosome profiling (Ribo-Seq) (maps positions of translating ribosomes on the transcriptome) and RNA-Seq (quantifies the transcriptome) analysis of African green monkey (Vero E6) cells and Aedes albopictus (C6/36) cells infected with Zika Virus (ZIKV) strain PE243. Cells were harvested at 24 h post infection (p.i.) and Ribo-Seq and RNA-Seq libraries were prepared and deep sequenced.
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Project description:Zika virus (ZIKV) is a mosquito-transmitted positive-sense RNA virus in the family Flaviviridae. Live attenuated vaccines have been successfully used to combat infection by flaviviruses, such as yellow fever and Japanese encephalitis viruses. A Zika virus harboring combined mutations in the envelope protein glycosylation site and in the nonstructural 4B protein amino acid 36 (ZE4B-36) was generated and assessed for stability, attenuation, and protection against infection. To determine the genetic stability of its RNA genome, ZE4B-36 was serially passaged in vitro in Vero cells. Virus harvested from passages (P)1 to P6 was subjected to next generation sequencing and downstream analysis to determine its nucleotide sequence variability. Specifically, single nucleotide variant analysis showed that the ZE4B-36 genome decreased its genetic diversity and resulted in a more stable nucleotide sequence. Thus, in addition to showing attenuation and protection, ZE4B-36 is a stable live attenuated virus that possesses characteristics important for a vaccine to combat Zika disease.
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Project description:The recent outbreaks of Zika virus (ZIKV) and its association with birth defects known as Congenital Zika Syndrome warrant investigation on the molecular processes related to its infection and pathogenesis. Among the flavivirus family, only ZIKV is linked to microcephaly as announced by World Health Organization, suggesting uniqueness of ZIKV infection compared to other members. By analyzing the ZIKV-host interactome, we found that the key microRNA (miRNA) processing enzyme Dicer was a leading target of ZIKV capsid protein in neural stem cells (NSCs), and its deficiency facilitated ZIKV infection. Mechanistically, ZIKV capsid can directly interact with Dicer and block its ribonuclease activity, dampening the production of host miRNAs that are essential for neurogenesis. Interestingly, this capsid-mediated immune evasion is specific to ZIKV because capsid proteins from other close flaviviruses, e.g., dengue, yellow fever and West Nile viruses, cannot bind to Dicer or inhibit its function. By molecular mapping, we defined a ZIKV capsid H41R mutant with loss of interaction to Dicer and no longer affecting its activity. More importantly, ZIKV H41R mutant exerted almost no impact on neurogenesis in vitro when expressed in NSCs compared to wild type capsid, and in utero infection of recombinant ZIKV-H41R mutant virus resulted in less inhibition on corticogenesis than wild-type ZIKV in mouse embryos. Interestingly, the epidemic ZIKV strain reinforces the capsid-Dicer interaction by two amino acid substitution compared to ancient Africa strain. Thus, our study demonstrated that capsid-dependent suppression of Dicer function is a unique determinant of ZIKV immune evasion and pathogenesis, which may unveil a new mechanism for ZIKV-mediated microcephaly.
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Project description:We repoted the Glioblastoma stem cells(GSCs) infected by two strains of ZIKA virus, the Brazil and Dakar strains. The ZIKV was added into the medium of GSCs for 48 hours, the RNA was harvested after ZIKV infection. We found that the GSCs up-regulated the Type 1&2 interferons after infected by ZIKV
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Project description:Although dendritic cells (DCs) are among the human cell population best equipped for cell-intrinsic antiviral immune defense, they seem highly susceptible to infection with Zika Virus (ZIKV). Using highly-purified mDC isolated from individuals with naturally-acquired acute infection, we here show that ZIKV induces profound perturbations of transcriptional signatures relative to uninfected patients. Interestingly, we noted a remarkable downregulation of antiviral Interferon-stimulated genes and innate immune sensors, suggesting that ZIKV can actively suppress Interferon-dependent immune responses. In contrast, several host factors known to support ZIKV infection were strongly upregulated during natural ZIKV infection; these transcripts included AXL, the main entry receptor for ZIKV, SOCS3, a negative regulator of ISG expression, and IDO-1, a recognized inducer of regulatory T cell responses. Thus, during in vivo infection, ZIKV can transform the transcriptome of dendritic cells in favor of the virus to render these cells highly conducive to ZIKV infection.
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Project description:Zika virus (ZIKV) is an emerging virus causally linked to neurological disorders, including congenital microcephaly and Guillain–Barré syndrome. There are currently no targeted therapies for ZIKV infection. To identify novel antiviral targets and to elucidate the mechanisms by which ZIKV exploits the host cell machinery to support sustained replication, we analyzed the transcriptomic landscape of human microglia, fibroblast, embryonic kidney, and monocyte-derived macrophage cell lines before and after ZIKV infection.
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