The Transcriptomic Consequences of Zika Virus Infection on Porcine Induced Neural Stem Cells and Associated Gene Regulatory Networks
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ABSTRACT:
ORGANISM(S): Sus scrofa
PROVIDER: GSE225413 | GEO | 2023/08/16
REPOSITORIES: GEO
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Project description:Here, we performed the first CRISPR-Cas9 genome-wide screen in glioblastoma stem cells (GSCs) to identify factors determining ZIKV neurotropism. Using a ZIKV-ZsGreen reporter virus, a new strategy was developed to sort infection-resistant cells, expand, and enrich the resistant pool. Importantly, bioinformatics analysis and functional validation revealed integrin αvβ5 as an internalization factor for ZIKV. Expression of αvβ5 is correlated with ZIKV susceptibility in various cell lines and matched the cell tropism in developing human cerebral cortex. Blocking antibody against integrin αvβ5 but not αvβ3 efficiently inhibited ZIKV infection. Mechanistic evaluation showed that ZIKV binds to cells but fails to internalize when treated with integrin αvβ5 blocking antibody. αvβ5 directly binds to ZIKV virions, activates FAK (focal adhesion kinase), which is required for ZIKV infection. Strikingly, pharmaceutical inhibitors of αvβ5, SB273005 and cilengitide suppressed ZIKV infection at nanomolar concentrations. Finally, αvβ5 blocking antibody or inhibitors reduced ZIKV infection and alleviated ZIKV induced pathology in human neural stem cells (hNSC) and in mouse brain. This is the first study, to the best of our knowledge, identifying integrin αvβ5 is an internalization factor for ZIKV providing a new therapeutic target as well as two promising drug candidates that potentially can be used as prophylactics or treatments for ZIKV infections.
2020-01-22 | GSE139142 | 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:Zika virus (ZIKV), a pathogen of global health concern, is transmitted to humans by Aedes mosquitoes. However, the molecular interactions between the vector and the virus remain largely unexplored. We demonstrated that ZIKV and dengue virus (DENV) have similar tropism and infection kinetics in two mosquito strains with different degrees of susceptibility to infection. Comparison of Aedes aegypti’s molecular responses to ZIKV and DENV infection indicated that around 40% of the mosquito’s infection-responsive transcriptome is virus-specific. Regulated genes also included key factors of the mosquito’s anti-viral immunity, pointing to the possible involvement of the Toll innate immune pathway. Comparison of ZIKV and DENV infection-responsive transcriptome data to those for yellow fever virus and West Nile virus identified 26 genes likely to play key roles in virus infection of Aedes mosquitoes. Through reverse genetic analyses, we showed that the Toll and the Jak/Stat innate immune pathways mediate increased resistance to ZIKV infection, and the virus use vATPase and inosine-5’-monophosphate dehydrogenase as mosquito’s host factors.
2017-11-07 | GSE96605 | GEO
Project description:Growing evidences have associated Zika virus infection with congenital malformations, including microcephaly. Nonetheless, signaling mechanisms that promote the disease outcome are far from being understood, affecting the development of suitable therapeutics. In this study, we applied shotgun mass spectrometry-based proteomics combined with cell biology approaches to characterize altered molecular pathways on neurons and NPCs infected by ZIKV-BR, strain obtained from the 2015 Brazilian outbreak. Assessment of neurons differentiated from iPSC from different donors shows the importance of the host genetic background to the susceptibility of ZIKV infection, also confirmed by cytokine fingerprinting. Additionally, infected cells presented an impairment of neurogenesis and synaptogenesis processes. Moreover, ZIKV-BR infected NPCs showed unique alteration of pathways involved in neurological diseases, cell death and survival and embryonic development compared to ZIKV-AF, showing a human adaptation of the Brazilian viral strain. Taken together, these data explain CNS developmental arrest observed in Congenital Zika Virus syndrome is beyond neuronal cell death.
2019-11-12 | PXD009293 | Pride
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) and dengue virus (DENV) are members of the Flaviviridae family of RNA viruses and cause severe disease in humans. ZIKV and DENV share over 90% of their genome sequences, however the clinical features of Zika and dengue infections are very different reflecting tropism and cellular effects. Here, we used simultaneous RNA sequencing and ribosome footprinting to define the transcriptional and translational dynamics of ZIKV and DENV infection in human neuronal progenitor cells (hNPCs). The gene expression data showed induction of aminoacyl tRNA synthetases (ARS) and the translation-activating PIM1 kinase indicating an increase in RNA translation capacity. The data also reveal activation of different cell stress reponses, with ZIKV triggering a BACH1/2 redox program, and DENV activating the ETF/CHOP endoplasmatic reticulum (ER) stress program. The RNA translation data highlight activation of polyamine metabolism through changes in key enzymes and their regulators. This pathway is needed for eIF5A hypusination and has been implicated viral translation and replication. Concerning the viral RNA genomes, ribosome occupancy readily identifies highly translated open reading frames and a novel upstream ORF (uORF) in the DENV genome. Together, our data highlight both the cellular stress response and also the activation of RNA translation and polyamine metabolism during DENV and ZIKV infection.
2022-07-06 | GSE207347 | GEO
Project description:Viral interfering RNA (viRNA) has been identified from several viral genomes via directly deep RNA sequencing of the virus-infected cells, including zika virus (ZIKV). Once produced by endoribonuclease Dicer, viRNAs, similar to microRNAs, are loaded onto Argonaute (AGO) family proteins of the RNA-induced silencing complexes (RISCs) to pair with their RNA targets and then initiate cleavage of the target genes. However, identities of functional ZIKV viRNAs and their viral RNA targets remain largely unknown. By combining AGO-associated RNA sequencing, deep sequencing analysis in ZIKV-infected neural stem cells (NSCs), and miRanda target scanning, we have defined 29 ZIKV derived viRNA profiles in NSCs, and established the complex interaction networks between the viRNAs and their viral targets. Our recent study has shown that ZIKV capsid protein interacted with Dicer and antagonized its endoribonuclease activity depending on its histidine (H) at the 41st amino acid. Accordingly, the rescued ZIKV-H41R mutant virus, compared to wild-type ZIKV, no longer suppressed Dicer enzymatic activity and consequently failed to inhibit miRNA biogenesis in NSCs. As a result, much higher levels of viRNAs generated from the ZIKV-H41R virus-infected NSCs, suggesting Dicer-dependent viRNA production. Knockdown of individual RNAi machinery in ZIKV-infected NSCs suggests that viRNA is a limiting factor of ZIKV infection in NSCs. The mapping of viRNAs to their RNA targets is paving a way to further investigate how viRNAs play the role in anti-viral mechanisms or even other unknown biological functions.
2021-02-16 | GSE159916 | GEO
Project description:We and others have demonstrated Zika virus (ZIKV) congenital infection evades double-stranded RNA detection, and may persist in the placenta for the duration of pregnancy without accompanying overt histopathologic inflammation. We used orthogonal approaches to test the hypothesis that ZIKV disrupts placental miRNAs to enable viral persistence and fetal pathogenesis. In primary human trophoblasts, high-throughput sequencing crosslinking and immunoprecipitation (AGO-HITS-CLIP) demonstrated an unexpected disruption of placental miRNA-regulated TGF-β networks. In gnotobiotic mice, absence of microbes rendered normally resistant mice susceptible to congenital ZIKV infection, and placental spatial transcriptomics revealed distinct microenvironments defined by significant upregulation of complement cascade components. Finally, treatment of ZIKV-infected mice with the RNAi-enhancer enoxacin led to loss of ZIKV placental persistence and rescue of fetal growth restriction. These results collectively suggest that ZIKV co-opts miRNA inflammatory regulatory networks to persist in the placenta reservoir, a conduit of vertical transmission and fetal pathogenesis.
2023-06-03 | GSE205631 | GEO
Project description:The re-emergence of Zika virus (ZIKV) in the Western Hemisphere has resulted in global public health crisis since 2015. ZIKV preferentially infects and targets human neural progenitor cells (hNPCs) and causes fetal microcephaly upon maternal infection. hNPCs not only play critical roles during fetal brain development, but also persist in adult brain throughout life. Yet the mechanism of innate antiviral immunity in hNPCs remains largely unknown. Here, we show that ZIKV infection triggers the abundant production of virus-derived small interfering RNAs in hNPCs, but not in the more differentiated progenies or somatic cells. Ablation of key RNAi machinery components significantly enhances ZIKV replication in hNPCs. Furthermore, enoxacin, a broad-spectrum antibiotic that is known as an RNAi enhancer, exerts potent anti-ZIKV activity in hNPCs and other RNAi-competent cells. Strikingly, enoxacin treatment completely prevents ZIKV infection and circumvents ZIKV-induced microcephalic phenotypes in brain organoid models that recapitulate human fetal brain development. Our findings highlight the physiological importance of RNAi-mediated antiviral immunity during the early stage of human brain development, uncovering a novel strategy to combat human congenital viral infections through enhancing RNAi.
2019-04-15 | GSE125520 | 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