MicroRNA-21 dysregulates the expression of MEF2C in neurons in monkey and human SIV/HIV neurological disease
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE55069 | GEO | 2014/02/18
SECONDARY ACCESSION(S): PRJNA238395
REPOSITORIES: GEO
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Project description:MicroRNAs (miRNAs) have important roles in regulating a plethora of physiological and pathophysiogical processes including neurodegeneration. In both human immunodeficiency virus (HIV)-associated dementia in humans and its monkey model simian immunodeficiency virus encephalitis (SIVE), we find miR-21, a miRNA largely known for its link to oncogenesis, to be significantly upregulated in the brain. In situ hybridization of the diseased brain sections revealed induction of miR-21 in neurons. miR-21 can be induced in neurons by prolonged N-methyl-D-aspartic acid receptor stimulation, an excitotoxic process active in HIV and other neurodegenerative diseases. Introduction of miR-21 into human neurons leads to pathological functional defects. Furthermore, we show that miR-21 specifically targets the mRNA of myocyte enhancer factor 2C (MEF2C), a transcription factor crucial for neuronal function, and reduces its expression. MEF2C is dramatically downregulated in neurons of HIV-associated dementia patients, as well as monkeys with SIVE. Together, this study elucidates a novel role for miR-21 in the brain, not only as a potential signature of neurological disease, but also as a crucial effector of HIV-induced neuronal dysfunction and neurodegeneration. Total cellular RNA was isolated from frozen (−80°C) brain specimens by using TRIzol (Invitrogen, Carlsbad, CA, USA) for the monkey samples, and RNAzol (Biotecx Laboratories, Houston, TX, USA) for the human samples, followed by column purification (miRNeasy, Qiagen, Valencia, CA, USA) as per manufacture's instructions. For the monkeys, four samples were from uninfected animals and four from SIV-infected animals that developed simian AIDS with SIV encephalitis. For the human samples, six samples were from individuals who were HIV negative with no history of dementia or neurocognitive disability and showed no significant neuropathology. Five samples were from HIV positive individuals that were neurocognitively impaired (NNTC clinical rating >6)38 and a neuropathological diagnosis of HIV encephalitis. Clinical information is provided in the supplemental material. For microarray analysis, only three of the HAD specimens were sufficient for use, but all five were used for the qRT-PCR studies.
2014-02-18 | E-GEOD-55069 | biostudies-arrayexpress
Project description:The etiology of the central nervous system (CNS) alterations after human immunodeficiency virus (HIV) infection, such as dementia and encephalitis, remains unknown. We have used microarray analysis in a monkey model of neuroAIDS to identify 98 genes, many previously unrecognized in lentiviral CNS pathogenesis, whose expression is significantly up-regulated in the frontal lobe of simian immunodeficiency virus-infected brains. Further, through immunohistochemical illumination, distinct classes of genes were found whose protein products localized to infiltrating macrophages, endothelial cells and resident glia, such as CD163, Glut5, and ISG15. In addition we found proteins induced in cortical neurons (ie, cyclin D3, tissue transglutaminase, 1-antichymotrypsin, and STAT1), which have not previously been described as participating in simian immunodeficiency virus or HIV-related CNS pathology. This molecular phenotyping in the infected brains revealed pathways promoting entry of macrophages into the brain and their subsequent detrimental effects on neurons. These data support the hypothesis that in HIV-induced CNS disease products of activated macrophages and astrocytes lead to CNS dysfunction by directly damaging neurons, as well as by induction of altered gene and protein expression profiles in neurons themselves which are deleterious to their function.
2008-06-12 | E-GEOD-2377 | biostudies-arrayexpress
Project description:The etiology of the central nervous system (CNS) alterations after human immunodeficiency virus (HIV) infection, such as dementia and encephalitis, remains unknown. We have used microarray analysis in a monkey model of neuroAIDS to identify 98 genes, many previously unrecognized in lentiviral CNS pathogenesis, whose expression is significantly up-regulated in the frontal lobe of simian immunodeficiency virus-infected brains. Further, through immunohistochemical illumination, distinct classes of genes were found whose protein products localized to infiltrating macrophages, endothelial cells and resident glia, such as CD163, Glut5, and ISG15. In addition we found proteins induced in cortical neurons (ie, cyclin D3, tissue transglutaminase, 1-antichymotrypsin, and STAT1), which have not previously been described as participating in simian immunodeficiency virus or HIV-related CNS pathology. This molecular phenotyping in the infected brains revealed pathways promoting entry of macrophages into the brain and their subsequent detrimental effects on neurons. These data support the hypothesis that in HIV-induced CNS disease products of activated macrophages and astrocytes lead to CNS dysfunction by directly damaging neurons, as well as by induction of altered gene and protein expression profiles in neurons themselves which are deleterious to their function. Keywords = HIV dementia Keywords = Gene array Keywords = Simian immunodeficiency virus Keywords = rhesus macaque Keywords: other
2005-03-08 | GSE2377 | GEO
Project description:Human immunodeficiency virus (HIV) is widely recognized for its striking impact on the immune system, and it also significantly impacts the central nervous system (CNS). The primary immune constituents in the brain, microglia and macrophages, are the target for HIV in people and the simian immunodeficiency virus (SIV) in nonhuman primates. This infection can lead to neurological dysfunction, known as HIV-associated neurocognitive disorder (HAND) and pathological entities such as HIV-induced encephalitis (HIVE). Given the gaps in our knowledge on how these cells respond in vivo to CNS infection, we performed single-cell multiomic sequencing, including gene expression and ATAC-seq on myeloid cells from the brains of two rhesus macaques with SIV-induced encephalitis (SIVE) as well as two uninfected controls. We used both RNA expression and chromatin accessibility to identify cell clusters. We found that the myeloid cell populations were significantly changed by SIVE, which differed greatly from those found in the uninfected brains. We categorized myeloid cells in the SIVE brains into two primary phenotypes: microglia-like and CAM-like, which were different from each other regarding trancriptomic profile and chromatin accessibility. We found that these microglia-like cells express high levels of chemoattractants for capable of recruiting highly the activated CAM-like cells to the site of infection/inflammation. Additionally, we observed a dramatic shift of upstream gene regulators and their targets in brain myeloid cells during SIVE. The transcription factors (TFs) highly enriched in SIVE-specific cell clusters were related to IRF/STAT and NF-κB mediated interferon and other proinflammatory cytokines production. Interestingly, some of these TF binding sites were also enriched in the open chromatin identified in the SIV DNA provirus in infected myeloid cells, indicating the immune activation in the host cells might also promote HIV/SIV gene expression and regulation . In summary, this study further uncover the trancriptome, gene regulaory events and potenital roles of differenet brain myeloid phenotypes in SIVE.
2024-10-15 | GSE272669 | GEO
Project description:Exosomes from the brains of rhesus macaques were isolated and characterized, both with and without simian immunodeficiency virus (SIV) induced central nervous system (CNS) disease. Small RNA sequencing revealed that exosomes from the brains of animals with CNS disease contained significantly increased miR-21, a microRNA we have previously shown to be significantly increased in both SIV and HIV induced CNS disease. In addition to neurons in the brain, macrophage/microglial cells/nodules also express miR-21 during SIV induced CNS disease. In vitro culture of macrophages revealed that miR-21 is released into exosomes, and exosomes from macrophage cultures produced from WT, but not miR-21-/- KO, animals are neurotoxic. We find this neurotoxicity is dependent upon exosome carriage of miR-21, and mutation of the sequence within miR-21 predicted to bind TLR7 eliminates this neurotoxicity. Indeed exosomal miR-21 activates TLR7 in a reporter cell line, and the neurotoxicity of exosomal miR-21 is dependent upon TLR7, as neurons isolated from TLR7-/- KO mice are protected from neurotoxicity. Finally, we show that exosomes isolated from the brains of monkeys with SIV induced CNS disease both activate TLR7 and are neurotoxic when compared to exosomes from control animals.
2018-01-29 | GSE109414 | GEO
Project description:Human immunodeficiency virus 1 (HIV-1) infects blood monocytes that cross the blood-brain barrier to the central nervous system inducing neuronal damage. This damage is prompted by the secretion of viral and neurotoxic factors by HIV-infected macrophages and can result in HIV associated neurocognitive disorders (HAND). One of these neurotoxic factors secreted by HIV-infected macrophages is cathepsin B (CATB), a lysosomal cysteine protease that plays an important role in neurodegeneration. CATB interacts with Serum Amyloid P component (SAPC) contributing to HIV-induced neurotoxicity. However, the neuronal apoptosis pathways triggered by CATB and SAPC remain unknown. We aimed to elucidate these pathways in neurons exposed to HIV-infected macrophage conditioned media (MCM) before and after inhibition of CATB or SAPC using Tandem Mass Tag (TMT) proteomics labeling. Based on significant fold change (FC) ≥ ǀ2ǀ and p-value < 0.05 criteria, a total of 10, 48 and 13 proteins were deregulated after inhibiting CATB, SAPC antibodies and the cathepsin B inhibitor CA-074, respectively. We found that antibodies against CATB and SAPC, as well as the CATB inhibitor CA-074 downregulated apoptosis related proteins. CATB, SAPC or apoptotic related proteins could become potential targets against HIV-induced neuronal degeneration.
2022-01-20 | PXD024636 | Pride
Project description:HIV-associated dementia (HAD) is a syndrome occurring in HIV-infected patients with advanced disease that likely develops as a result of macrophage and microglial activation as well as other immune events triggered by virus in the central nervous system. The most relevant experimental model of HAD, rhesus macaques exhibiting SIV encephalitis (SIVE), closely reproduces the human disease and has been successfully used to advance our understanding of mechanisms underlying HAD. In this study we integrate gene expression data from uninfected and SIV-infected hippocampus with a human protein interaction network and discover modules of genes whose expression patterns distinguish these two states, to facilitate identification of neuronal genes that may contribute to SIVE/HIV cognitive deficits. Using this approach we identify several downregulated candidate genes and select one, EGR1, a key molecule in hippocampus-related learning and memory, for further study. We show that EGR1 is downregulated in SIV-infected hippocampus and that it can be downregulated in differentiated human neuroblastoma cells by treatment with CCL8, a product of activated microglia. Integration of expression data with protein interaction data to discover discriminatory modules of interacting proteins can be usefully employed to prioritize differentially expressed genes for further study. Investigation of EGR1, selected in this manner, indicates that its downregulation in SIVE may occur as a consequence of the host response to infection, leading to deficits in cognition. RNA from duplicate hippocampal samples taken from nine control monkeys and nine monkeys with evidence of SIV encephalitis were hybridized to Affymetrix arrays.
2010-04-03 | E-GEOD-13824 | biostudies-arrayexpress
Project description:HIV-associated dementia (HAD) is a syndrome occurring in HIV-infected patients with advanced disease that likely develops as a result of macrophage and microglial activation as well as other immune events triggered by virus in the central nervous system. The most relevant experimental model of HAD, rhesus macaques exhibiting SIV encephalitis (SIVE), closely reproduces the human disease and has been successfully used to advance our understanding of mechanisms underlying HAD. In this study we integrate gene expression data from uninfected and SIV-infected hippocampus with a human protein interaction network and discover modules of genes whose expression patterns distinguish these two states, to facilitate identification of neuronal genes that may contribute to SIVE/HIV cognitive deficits. Using this approach we identify several downregulated candidate genes and select one, EGR1, a key molecule in hippocampus-related learning and memory, for further study. We show that EGR1 is downregulated in SIV-infected hippocampus and that it can be downregulated in differentiated human neuroblastoma cells by treatment with CCL8, a product of activated microglia. Integration of expression data with protein interaction data to discover discriminatory modules of interacting proteins can be usefully employed to prioritize differentially expressed genes for further study. Investigation of EGR1, selected in this manner, indicates that its downregulation in SIVE may occur as a consequence of the host response to infection, leading to deficits in cognition.
2009-08-29 | GSE13824 | GEO
Project description:The virus/host interactions during the acute phase of human immunodeficiency virus (HIV) infection help determine the course of disease. During this time period, virus enters the brain. Here, we report clusters of genes whose transcripts are significantly upregulated in the frontal lobe of the brain during acute simian immunodeficiency virus (SIV) infection of rhesus monkeys. Many of these genes are involved in interferon (IFN) and/or interleukin (IL)-6 pathways. Although neither IFNa nor IFN? are elevated in the brain, IL6 is increased. Both IFNa and IL6 are elevated in plasma during this acute phase. The upregulation of STAT1, verified by immunohistochemical staining, can be due to both central nervous system (CNS) (SIV and IL6) and peripheral (IFNa and IL6) causes, and can itself drive the expression of many of these genes. Examination of the levels of expression of the upregulated genes in the post-acute and long-term phases of infection, as well as in SIV encephalitis, reveals increased expression throughout SIV infection, which may serve to protect the brain, but can have untoward long-term consequences. Keywords = HIV dementia Keywords = Gene array Keywords = Cytokine Keywords = Simian immunodeficiency virus Keywords: other
2005-03-10 | GSE2393 | GEO
Project description:Over the last decade, small noncoding RNA molecules such as microRNAs (miRNAs) have emerged as critical regulators in the expression and function of eukaryotic genomes. It has been suggested that viral infections and neurological disease outcome may also be shaped by the influence of small RNAs. This has prompted us to suggest that HIV infection alters the endogenous miRNA expression patterns, thereby contributing to neuronal deregulation and AIDS dementia. Therefore, using primary cultures and neuronal cell lines, we examined the impact of a viral protein (HIV-1 Tat) on the expression of miRNAs due to its characteristic features such as release from the infected cells and taken up by noninfected cells. Using microRNA array assay, we demonstrated that Tat deregulates the levels of several miRNAs. Interestingly, miR-34a was among the most highly induced miRNAs in Tat-treated neurons. Tat also decreases the levels of miR-34a target genes such as CREB protein as shown by real time PCR. The effect of Tat was neutralized in the presence of anti-miR-34a. Using in situ hybridization assay, we found that the levels of miR-34a increase in Tat transgenic mice when compared with the parental mice. Therefore, we conclude that deregulation of neuronal functions by HIV-1 Tat protein is miRNA-dependent. Human fetal neurons were chosen to examine the impact of HIV-1 Tat protein on gene expression
2012-12-07 | E-GEOD-42423 | biostudies-arrayexpress