An Integrated Systems Analysis Implicates EGR1 Downregulation in Simian Immunodeficiency Virus Encephalitis-Induced Neural Dysfunction

Abstract

Human immunodeficiency virus (HIV)-associated dementia (HAD) is a syndrome occurring in HIV-infected patients with advanceddisease 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 simian immunodeficiency virus (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 used 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.

Zif268 / Egr1 gain of function facilitates hippocampal synaptic plasticity and long-term spatial recognition memory

“…Finally, Zif268 can mediate epigenetic programming via DNA methylation and histone posttranslational modifications to influence downstream gene regulation [42,43]. Down-regulation of Zif268 has been observed in ageing or certain diseases leading to cognitive deficits [44][45][46]. Selective intervention on these epigenetic mechanisms at the Zif268 rstb.royalsocietypublishing.org Phil.…”

Genetic, Transcriptomic, and Epigenetic Studies of HIV-Associated Neurocognitive Disorder

“…Such studies, generally limited to examination of homogenized frontal grey matter tissue, have found altered regulation of genes involved in neuroimmune functioning, and also implicated neurodegenerative pathways based on dysregulation of genes involved in synapto-dendritic functioning and integrity 136 , toll-like receptors 137 , and interferon response 138 . As recently reviewed 139 , findings from human microarray studies have been partially replicated in simian immunodeficiency virus (SIV) models, especially with regards to interferon-related and neuroinflammatory-related genes 140,141 . Mouse astrocytes exposed to HIV have also shown some transcription overlap with those of simian and human studies 142 .…”

Infection-Associated Dementia

“…23 Suatu observasi menunjukkan bahwa gejala klinis demensia terkait infeksi berkorelasi dengan mikroglia yang teraktivasi. 24 Dalam suatu penelitian diketahui bahwa derajat beratnya demensia terkait infeksi juga ditentukan oleh jumlah astrosit yang teraktivasi. 25 Astrosit mampu menghasilkan mediator inflamasi penyebab terjadinya disrupsi homeostasis neuronal, sehingga aktivasi astrosit ikut berkontribusi terhadap terjadinya neuropatologi yang terkait dengan infeksi SSP.…”

“…Kerusakan neuron tersebut selanjutnya mencetuskan terjadinya disfungsi dan kematian sel neuron dan glia. 24 Mediator proinflamasi juga mengganggu ambilan glutamat oleh astrosit, sehingga terjadi aktivasi reseptor NMDA dan stres oksidatif. Indikator patologis dari kerusakan dan kematian neuron 28 Observasi terakhir juga menunjukkan bahwa Treponema pallidum dan Borrelia burgdoferi mengandung protein amiloidogenik.…”