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Plasmodium falciparum HRP2-mediated brain cortical organoid damage is Toll-Like Receptor dependent and is attenuated via Neuregulin-1/ErbB4 signaling

ABSTRACT: Human cerebral malaria (HCM) is a severe complication of Plasmodium falciparum infection associated with high mortality rates predominantly in children that live in sub-Saharan Africa. Histine rich protein 2 (HRP2) is a diagnostic and prognostic marker that can be detected in peripheral blood, cerebrospinal fluid and cord blood. Recent studies confirm that HRP2 crossess the compromised blood brain barrier (BBB) during HCM and infiltrate brain parenchyma. Treatments with HRP2 in murine experimental cerebral malaria (ECM) model recapitulate these effects. We tested the hypothesis that treatment of induced pluripotent stem cells (iPSC)-derived brain cortical organoids with HRP2 will recapitulate the brain effects. We assessed the effects of HRP2 treatment on ultrastructure, expression of markers of viability and inflammation neurons, astrocytes and microglia in organoids. We tested the neuroprotective effects of Neuregulin 1 (NRG1) against the HRP2 treatment. In the study presented here, we assessed the inflammatory genes induced by HRP2 using the Immunology Panel on the nCounter system (NanoString) and results were analyzed using nSolver softaware.

ORGANISM(S): Homo sapiens

PROVIDER: GSE172366 | GEO | 2021/12/01

REPOSITORIES: GEO

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Plasmodium falciparum HRP2-induced damage to brain cortical organoids damage is Toll-Like Receptor dependent and is attenuated via Neuregulin-1/ErbB4 signaling

Project description:Human cerebral malaria (HCM) is a severe complication of Plasmodium falciparum (P.f.) infection that is characterized by capillary occlusions, rupture of the blood-brain barrier (BBB) and perivascular cellular injury. P.f. histidine-rich protein 2 (HRP2), a byproduct of parasitized red blood cell (pRBC) lysis, crosses the BBB when compromised to cause brain injury. We hypothesized that HRP2-induced neuronal damage can be attenuated by Neuregulin 1 (NRG1), an anti-inflammatory neuroprotective factor. Using brain cortical organoids, we determined that HRP2 upregulated cell death and inflammatory markers and disorganized brain organoid tissue. We identified Toll Like Receptors (TLR1 and 2) as potential mediators of HRP2-induced cellular damage and inflammation. Exogenous treatment of organoids with NRG1 attenuated HRP2 effects. The results indicate that HRP2 mediates malaria-associated HRP2-induced brain injury and inflammation and that NRG1 may be an effective therapy against HRP2 effects in the brain. In the study presented here, we assessed the inflammatory genes induced by HRP2 using the Immunology Panel on the nCounter system (NanoString) and results were analyzed using nSolver softaware.

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RNA-seq analysis of anti-malarial drug chemotherapy of murine experimental Cerebral Malaria (ECM)

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HRP2-MINA complex reprograms t(4;14) multiple myeloma epigenome to dictate chemosensitivity to proteasome inhibitors [RNA-Seq]

Project description:Depletion of HRP2 induced remarkable resistance to PIs induced apoptosis of MM cells in vitro and in vivo, and suppressed expression of HRP2 was observed in bortezomib-resistant (BR) MM cells. Notably, HRP2 altered chemosensitivity more obviously in MM cells with t(4;14) translocation, and much remarkable resistant to PIs than other reagents. Moreover, HRP2 abolition of HRP2 augmented H3K27me3 modification, consequentially intensifying transcriptome alteration prone to cell survival and restriction of endoplasmic reticulum (ER) stress. Mechanistically, HRP2 recognized H3K36me2 and recruited the histone demethylases MYC-induced nuclear antigen (MINA) to degrade H3K27me3, released suppression on genes responsible for drug resistance, such as ATF3 and NR4A1. Thus, an EZH2 inhibitor, tazemetostat, synergistically sensitized anti-MM effect of bortezomib both in vitro and in vivo. Collectively, our study provides novel knowledge to understand the origination of chemoresistance in MM patients with t(4;14), and rationale for managing MM patients according to different genomic backgrounds.

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Trans-omic Profiling Uncovers Molecular Controls of the Early Human Cerebral Organoid Formation

Project description:Defining molecular controls that orchestrate human brain development is essential for uncovering the complexity behind neurodevelopment and the pathogenesis of neurological disorders. Due to the difficulties in accessing embryonic and fetal brain tissues, the differentiation of human pluripotent stem cell (hPSC)-derived three-dimensional neural organoids has made it possible to recapitulate this developmental process in vitro and provide a unique opportunity to investigate human brain development and disease. To elucidate the molecular programs that drive this highly dynamic process, here, we generate a comprehensive trans-omic map of the phosphoproteome, proteome, and transcriptome of the initial stages of pluripotency and neural differentiation towards the formation of cerebral organoids. Our integrative analysis uncovers key phospho-signalling events underlying neural lineage differentiation, and their convergence on transcriptional (co-)factors and chromatin remodellers that govern downstream gene regulatory networks (GRNs). Comparative analysis with developing human and mouse embryos using these GRNs demonstrates the fidelity of our early cerebral organoids in modelling embryonic brain development. Finally, we demonstrate biochemical modulation of the AKT signalling as a key molecular switch for controlling human cerebral organoid formation. Our data provides a comprehensive resource to gain insight into the molecular controls in human embryonic brain development and also provide a guide for future development of protocols for human cerebral organoid differentiation.

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HRP2-DPF3a-BAF complex coordinates histone modification and chromatin remodeling to regulate myogenic gene transcription [ChIP-Seq]

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HRP2-DPF3a-BAF complex coordinates histone modification and chromatin remodeling to regulate myogenic gene transcription [RNA-Seq]

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2020-05-13 | GSE148294 | GEO

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Project description:Human cerebral cortex development is a highly complex and orchestrated process that is under tight genetic regulation. Rare mutations that alter gene expression or function can disrupt the structure of the cerebral cortex, resulting in a variety of neurological cAonditions1. Lissencephaly (“smooth brain”) spectrum disorders comprise a group of rare, genetically heterogeneous congenital brain malformations commonly associated with epilepsy and intellectual disability2. However, the molecular mechanisms underlying disease pathogenesis remain unknown. Here, we establish hypoactivity of the mammalian target of rapamycin (mTOR) pathway as a clinically relevant molecular mechanism in lissencephaly spectrum disorders. We characterized cerebral organoids from individuals with two genetically distinct lissencephalies harboring a recessive mutation in P53-Induced Death Domain Protein 1 (PIDD1) or a heterozygous chromosome 17p13.3 microdeletion leading to Miller-Dieker Lissencephaly Syndrome (MDLS). We found that PIDD1-mutant and MDLS organoids recapitulate the thickened cortex typical of human lissencephaly and demonstrated dysregulation of protein translation, metabolism, and the mTOR pathway. We found that a brain-selective activator of mTOR complex 1 (mTORC1) prevents, and even reverses, cellular and molecular defects in lissencephaly organoids. Our findings unveil an unexpected converging molecular mechanism contributing to genetically heterogeneous lissencephaly spectrum disorders.

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