Project description:Dengue virus is the most common arbovirus worldwide and represents a significant public health concern. To date, chronic Dengue infections have not been previously reported. While investigating the etiology of central nervous system (CNS) disease in a patient presenting with progressive dementia, we elucidated a chronic dengue infection within the CNS. Comprehensive viral immune responses in both serum and cerebrospinal fluid (CSF) were profiled by a phage-display assay (VirScan). Enrichment of Dengue viral antibodies were detected in the CSF as compared to the serum. No virus was detected in serum or CSF, but post-mortem analysis confirmed Dengue virus in the brain by quantitative polymerase chain reaction (PCR), immunohistochemistry, RNAscope and sequencing. Dengue virus was detectable by PCR and sequencing from brain biopsy tissue collected 33 months ante-mortem, confirming a chronic infection. Comprehensive antibody profiling assays can aid in the diagnosis of encephalitis of unknown etiologies. Our findings suggest that Dengue virus infections may persist in the CNS and should be considered in patients with progressive dementia in endemic regions or with relevant travel history.
Project description:Finding the differences in gene expression in three regions of the brai, basal ganglia, white matter, and frontal cortex, in normal, HIV infected, HIV inefected with neurocognitive impairment, and HIV infected with both neurocognitive impairment and encephalitis patients. We used microarrays to identify differentially expressed genes in normal, HIV infected, HIV inefected with neurocognitive impairment, and HIV infected with both neurocognitive impairment and encephalitis patients. Samples from three different brain regions from normal, HIV infected, HIV infected with neurocognitive impairment (HAD: HIV-associated dementia), and HIV infected with both neurocognitive impairment and encephalitis (HIVE: HIV encephalitis) patients were collected for RNA isolation and supsequent Affymetrix microarray analysis. We sought to obtain gene expression levels in different brain regions to find implication of HIV and the neurological impairment and inflammation associated with HIV infection.
Project description:Rasmussen encephalitis is a unilateral encephalitis characterized by treatment-resistant epilepsy and progressive cognitive and motor decline. MRI reveals inflammation and neuropathology reveals reactive astrocytes, microglial activation, microglial nodules, T cell infiltration, and neuronal loss.
Despite the abundant evidence of altered signaling pathways in Rasmussen brain tissue and associated genetic variants, the mechanisms remain poorly understood, and it is uncertain which are a part or result of the underlying cause
In Rasmussen brain tissue, we identified by RNAseq altered immune signaling pathways, immune cell type annotation enrichment, and by whole exome sequencing HLA variants more common to Rasmussen. These findings demonstrate immune cell infiltration associated with innate and adaptive immune responses, as well as HLA variants that may increase vulnerability to RE.
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.
Project description:Around 25% of stroke survivors over 65 years old develop progressive cognitive decline more than 3 months post-stroke, with features of vascular dementia. Poststroke dementia (PSD) is associated with pathology in frontal brain regions, in particular dorsal lateral prefrontal cortex (DLPFC) neurons and white matter, remote from the infarct, implicating damage to anterior cognitive circuits (ACC) involved in impaired executive function. We hypothesised that PSD results from progressive neuronal damage in the DLPFC and that this is associated with alterations in the gliovascular unit (GVU) of frontal white matter. We aimed to identify the cellular and molecular basis of PSD by investigating the transcriptomic profile of the neurons and white matter GVU cells previously implicated in pathology. Laser capture microdissected neurons, astrocytes and endothelial cells were obtained from the Cognitive Function After Stroke (COGFAST) cohort. Gene expression was assessed using microarrays and pathways analysis to compare changes in PSD with controls and with poststroke non-dementia (PSND). Laser captured microdissected neurons were obtained from the bilateral carotid artery stenosis (BCAS) model and equivalent SHAM animals
Project description:Human cerebrospinal fluid was collected from patients diagnosed with neurodegenerative diseases including multiple system atrophy (n=28), Parkinson’s disease (n=40), dementia with Lewy bodies (n=20), progressive supranuclear palsy (n=39) and from controls (n=17) in order to perform a comparative quantitative proteome profiling of cerebrospinal fluids from the five groups.
Project description:Dengue virus is an + strand RNA virus. We have carried our infections of human cells with Dengue and analyzed the translation, replication, and localization of the Dengue RNA. This allowed for clear definition of the life cycle of the Dengue virus inside a host cell. We also assessed the host response to Dengue virus, finding that a large fraction of the translational response is due to Interferon function. Translational and transcriptional analysis of the cellular response to Dengue virus infection