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Systems analysis of viral infection in the embryonic central nervous system (CNS)

ABSTRACT: A new mouse model for congenital Zika infection in a wildtype, immunocompetent background employing intraplacental infection resulted in productive infection of embryonic brains and features of microcephaly during early development (E10.5-16.5). Gross morphological characterization showed translational relevance for understanding the viral neuropathogenesis and Zika-associated microcephaly in humans. Thus, an integrated, multi-omics (RNA-sequencing, proteomics) analysis of fetal brain tissues was performed to understand pathways perturbed by viral infection in developing brains. These analyses identified virus-induced defects in cell cycle progression and neurodevelopment, in S-phase DNA replication and NEUROD2/TBR2 transcription factor cascades, respectively. Among the most significant responses was induction of innate immune programs in ZIKV-infected brains, including immunoproteasome activation and MHC-I antigen display associated with immune cell infiltration and neuronal death during early development. Identification of specific components within major pathways contributing to viral infection-induced effects on neurodevelopment provides novel targets for therapeutic intervention against neurotropic infections and ZIKV-associated microcephaly specifically.

ORGANISM(S): Mus musculus

PROVIDER: GSE118935 | GEO | 2021/08/21

REPOSITORIES: GEO

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Integrative systems biology characterizes immune-mediated neurodevelopmental changes in murine Zika Virus microcephaly

Project description:A new mouse model for congenital Zika infection in a wildtype, immunocompetent background employing intraplacental infection resulted in productive infection of embryonic brains and features of microcephaly during early development (E10.5-16.5). Gross morphological characterization showed translational relevance for understanding the viral neuropathogenesis and Zika-associated microcephaly in humans. Thus, an integrated, multi-omics (RNA-sequencing, proteomics) analysis of fetal brain tissues was performed to understand pathways perturbed by viral infection in developing brains. These analyses identified virus-induced defects in cell cycle progression and neurodevelopment, in S-phase DNA replication and NEUROD2/TBR2 transcription factor cascades, respectively. Among the most significant responses was induction of innate immune programs in ZIKV-infected brains, including immunoproteasome activation and MHC-I antigen display associated with immune cell infiltration and neuronal death during early development. Identification of specific components within major pathways contributing to viral infection-induced effects on neurodevelopment provides novel targets for therapeutic intervention against neurotropic infections and ZIKV-associated microcephaly specifically.

2023-03-06 | MSV000091415 | MassIVE

Molecular Signatures Associated with ZIKV Exposure in Human Cortical Neural Progenitors and Astrocytes

Project description:Zika virus (ZIKV) infection causes microcephaly and has been linked to other brain abnormalities. How ZIKV impairs brain development and function remains elusive. Here we systematically profiled transcriptomes of human neural progenitor cells (hNPCs) and astrocytes exposed to Asian ZIKVC, African ZIKVM, and Dengue virus (DENV). DENV causes distinct gene expression changes; and ZIKV has a broader impact on the expression of gene involved in DNA replication and repair. While overall expression profiles are similar, ZIKVC, but not ZIKVM, induces upregulation of viral response genes. Upon ZIKV infection, astrocytes exhibit more prominent transcriptome changes than hNPCs, particularly enriching genes related to inflammatory response and cytokine production pathways. Our analyses reveal cell-type- and strain-specific molecular signatures associated with ZIKV infection, and identify astrocytes as a major direct target of ZIKV. Further investigation of ZIKV-host interactions based our transcriptomic datasets may help to illuminate neural virulence determinants of ZIKV in patients. Gene Expression Analyses of the cells infected with different flaviviruses

2016-08-23 | E-GEOD-80434 | biostudies-arrayexpress

Differentiation enhances Zika virus infection in neuronal brain cells

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

Inter and intra-lineage genetic diversity of Zika virus differs for American isolates

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

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Project description:Zika virus (ZIKV) infection causes microcephaly and has been linked to other brain abnormalities. How ZIKV impairs brain development and function remains elusive. Here we systematically profiled transcriptomes of human neural progenitor cells (hNPCs) exposed to Asian ZIKVC, African ZIKVM, and Dengue virus (DENV). DENV causes distinct gene expression changes; and ZIKV has a broader impact on the expression of gene involved in DNA replication and repair. While overall expression profiles are similar, ZIKVC, but not ZIKVM, induces upregulation of viral response genes. Our analyses reveal virus- and strain-specific molecular signatures associated with ZIKV infection. Further investigation of ZIKV-host interactions based our transcriptomic datasets may help to illuminate neural virulence determinants of ZIKV in patients.

2016-08-23 | GSE80434 | GEO

Discovery of Drug Candidates that Inhibit and Eliminate Zika Virus Infection in Fetal and Adult Brain

Project description:Zika virus (ZIKV) infects fetal and adult human brains, and is associated with serious neurological complications including microcephaly and Guillain-Barré Syndrome (GBS). To date, no prophylactic or therapeutic treatment is available to prevent or treat ZIKV infection. Here, we performed a high content chemical screen using a library containing FDA-approved drugs or drug candidates. Two compounds, hippeastrine hydrobromide (HH) and amodiaquine dihydrochloride dihydrate (AQ), were discovered to inhibit ZIKV infection in human cortical neuron progenitor cells (hNPCs). HH was further validated to inhibit ZIKV infection and to rescue ZIKV-induced growth and differentiation defects in hNPCs and human fetal-like forebrain organoids. Finally, HH and AQ suppressed ZIKV infection in adult mouse brain in vivo. Strikingly, HH and AQ fully rescued the severe limb paralysis syndrome developed in ZIKV infected adult mice. This study identifies drug candidates for treatment of ZIKV infection and ZIKV-related neurological complications in fetal and adult patients.

2017-07-06 | GSE89334 | GEO

Host and genetic viral adaptations enable development of an immunocompetent mouse model of Zika virus infection

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.

2018-04-05 | GSE112711 | GEO

Zika virus infection reprograms global transcription of host cells to allow sustained infection

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.

2017-03-01 | GSE93870 | GEO

LC-MS/MS - NS-NE - Zika Virus Impairs Neurogenesis and Synaptogenesis Pathways in Human Neural Stem Cells and Neurons

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

Virus-Host Interactome Reveals the Unique Blockage of Host RNAi Machinery by the Zika Virus Capsid

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

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