Single cell transcriptome atlas revealed the feature of contemporary ZIKA virus induced microcephaly in mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE233624 | GEO | 2026/06/01
REPOSITORIES: GEO
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Project description:Background: Zika virus (ZIKV) is a neurotropic flavivirus. The outbreak of ZIKV in 2016 created a global health emergency. However, the underlying pathogenic mechanisms remain elusive. Methods: We investigated the host response features of in vivo replication in a mouse model of ZIKV infection, by performing a series of transcriptomic and bioinformatic analyses of ZIKV and mock-infected brain tissue. Results: Tissue damage, inflammatory cells infiltration and high viral replication were observed in the brain tissue of ZIKV infected mice. RNA-Seq of the brain indicated the activation of ferroptosis pathways. Enrichment analysis of ferroptosis regulators revealed their involvement in pathways such as mineral absorption, fatty acid biosynthesis, fatty acid degradation, PPAR signaling pathway, peroxidase and adipokinesine signalling pathway. We then identified 12 interacted hub ferroptosis regulators (CYBB, HMOX1, CP, SAT1, TF, SLC39A14, FTL, LPCAT3, FTH1, SLC3A2, TP53 and SLC40A1) that were related to the differential expression of CD8+ T cells, microglia and monocytes. CYBB, HMOX1, SALT and SLAC40A1 were selected as potential biomarkers of ZIKV infection. Finally, we validated our results using RT-qPCR and outside available datasets. Conclusions: For the first time, we proposed a possible mechanism of ferroptosis in brain tissue infected by ZIKV in mice and identified the four key ferroptosis regulators.
2022-12-06 | GSE213898 | GEO
Project description:The suspected link between infection by Zika virus (ZIKV), a re-emerging flavivirus, and microcephaly, is an urgent global health concern. The direct target cells of ZIKV in developing human fetuses are not clear. Here we show that ZIKV serially passaged in monkey and mosquito cell lines infects human induced pluripotent stem cells (hiPSCs)-derived cortical neural progenitor cells (hNPCs) with much higher efficiency compared to hiPSCs and hNPC-derived immature cortical neurons. Infected hNPCs produces infectious ZIKV particles. Importantly, ZIKV infection increases cell death and dysregulates cell cycle progression, resulted in attenuated hNPC growth. RNA-sequencing analysis of infected hNPCs further reveals transcriptional dysregulation, notably genes in cell cycle pathways. Our results identify human cortical neural precursors as a major and direct target of ZIKV infection and establish a tractable experimental model system to investigate the impact and mechanism of ZIKV on human brain development and a platform to screen therapeutic compounds.
2016-03-04 | GSE78711 | GEO
Project description:Zika virus (ZIKV) of the Flaviviridae family is a recently emerged mosquito-borne virus that has been implicated in the surge of the number of microcephaly instances in south America. The virus is transmitted mainly by the mosquito Aedes aegypti that also vectors dengue virus. Considering rather recent rapid spread of the virus and its declaration as a global health emergency by the World Health Organization, little is known about the interactions of the virus with the mosquito vector. In this study, we investigated the transcriptome profiles of whole Ae. aegypti mosquitoes in response to ZIKV infection at 2, 7 and 14 days post-infection using deep sequencing. Results showed a large number of transcripts were altered at each time point following infection, but 18 transcripts were commonly changed at the three time points. The outcomes provide a basic understanding of Ae. aegypti responses to ZIKV and help determining host factors involved in replication or anti-viral response against the virus.
2017-10-27 | GSE102939 | GEO
Project description:Zika virus (ZIKV), a flavivirus transmitted primarily by Aedes mosquitoes, has spread to 59 countries and territories throughout the world. ZIKV-infected patients can have several symptoms and there is scientific consensus that ZIKV is a cause of microcephaly. Most studies are focusing on the central nervous system (CNS), and it is largely unknown whether ZIKV also affects the developing peripheral nervous system. Here, using a human pluripotent stem cell-based model, we demonstrated that Puerto Rican ZIKV strain, PRVABC59, efficiently infects human neural crest cells (hNCCs). In contrast to little infection of CNS neurons, ZIKV readily infects human peripheral neurons (hPNs), leading to cell death. Global gene expression analyses of infected hNCCs and hPNs reveal transcriptional dysregulation, notably of cell-death- and cell-cycle-related pathways. Our results identify hNCCs and hPNs as a direct ZIKV target and provide a framework to investigate the ZIKV pathology on the peripheral neurons.
2017-07-07 | GSE87750 | GEO
Project description:Human infection with the flavivirus ZIKA (ZIKV) causes severe neurological, immunological, and developmental defects. Despite recent progress, the mechanisms by which ZIKV infection alters host transcriptional and translational programs remains unclear. Here, we report that ZIKV infection has profound effects on the topology and function of N6-adenosine methylation (m6A) of both viral and human RNAs. m6A and 2′-O-methylated nucleosides are abundant in ZIKV genomic RNA, and m6A-seq identified 12 m6A peaks spanning the full length of ZIKV RNA. m6A abundance in ZIKV RNA is controlled by the host methyltransferases METTL3 and METTL14 and the demethylase ALKBH5. Profiling of the m6A methylome of host mRNAs revealed that ZIKV infection alters the location of m6A in mRNAs, the methylation motifs, and the target genes modified by the methyltransferases. Our results identify a new mechanism by which ZIKV interacts with and alters the function of the host cell.
2016-11-15 | GSE87516 | GEO
Project description:Purpose and Methods: To profile m6A modifications on both the viral genome RNA and cellular transcripts, we used Methylated RNA immunoprecipitation sequencing (MeRIP-seq) on ZIKV SZ1901-infected human hepatocarcinoma cell line Huh7. Results and conclusions: Using MeRIP-seq, we identified a unique m6A map in the genome of ZIKV strain SZ1901 that is different from all previous isolates. Our study describes unique viral and host m6A profiles in contemporary ZIKV-infected Huh7 cells, highlighting the complexity and importance of m6A modification during viral infection.
2022-08-22 | GSE203043 | GEO
Project description:We explored the utility of oncolytic virus therapy against glioblastoma with Zika virus (ZIKV), a flavivirus that induces cell death and differentiation of neural precursor cells in the developing fetus. ZIKV preferentially infected and killed glioblastoma stem cells (GSCs) relative to differentiated tumor progeny or normal neuronal cells. The effects against GSCs were not a general property of neurotropic flaviviruses, as West Nile Virus (WNV) indiscriminately killed both tumor and normal neural cells. ZIKV potently depleted patient-derived GSCs grown in culture and in organoids. Moreover, mice with glioblastoma survived substantially longer and at greater rates when the tumor was inoculated with a murine adapted strain of ZIKV. Our results suggest that ZIKV is an oncolytic virus that can preferentially target GSCs, and thus, genetically modified strains that further optimize safety could have therapeutic efficacy for adult glioblastoma patients.
2017-08-23 | GSE102244 | GEO
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.
2020-08-04 | GSE137592 | GEO
Project description:The Zika virus (ZIKV) is a mosquito-borne Flavivirus and can be transmitted through an infected mosquito bite or through human-to-human interaction by sexual activity, blood transfusion, breastfeeding or perinatal exposure. After the 2015-2016 outbreak in Brazil, a strong link between ZIKV infection and microcephaly emerged. ZIKV specifically targets human neural progenitor cells, suggesting that proteins encoded by ZIKV bind and inactivate host cell proteins leading to microcephaly. Here, we present a systematic annotation of interactions between human proteins and the seven non-structural ZIKV proteins corresponding to a Brazilian isolate. The interaction network was generated by combining tandem-affinity purification followed by mass spectrometry with yeast two-hybrid screens. We identified 150 human proteins, involved in distinct biological processes, as interactors to ZIKV non-structural proteins. Our interacting network is composed of proteins that have been previously associated with microcephaly in human genetic disorders and/or animal models. This study builds on previously published interacting networks of ZIKV and genes related to autosomal recessive primary microcephaly to generate a catalog of human cellular targets of ZIKV proteins implicated in processes related to microcephaly in humans. Collectively, this data can be used as a resource for future characterization of ZIKV infection biology and help create a basis for the discovery of drugs which may disrupt the interaction and reduce the health damage to the fetus.
2020-06-18 | PXD014961 | Pride
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