Unknown,Transcriptomics,Genomics,Proteomics

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Genome-wide analysis of gene expression profiles in individuals infected with the Human T-Lymphotropic virus Type 1 (HTLV-1) - train set

ABSTRACT: Infection with the human T lymphotropic virus type 1 (HTLV-1) remains asymptomatic in the majority of carriers; however, some 5% develop a chronic inflammation of the central nervous system termed HTLV-1-associated myelopathy (HAM). It is not well understood how the virus triggers the onset of HAM after many years of clinical latency and importantly, what distinguishes hosts who develop the disease from those who remain asymptomatic. In this study we tested the hypothesis that patients with HAM can be distinguished from asymptomatic HTLV-1 carriers (ACs) and uninfected subjects by their whole blood transcriptional profiles. Here, we compare unstimulated whole blood gene expression profiles of 20 asymptomatic HTLV-1 carriers (ACs), 10 patients with HAM and 9 uninfected healthy control subjects to (1) identify a transcriptional signature associated with presence of HAM and (2) identify cell types and pathways abnormally regulated in HAM by canonical and modular pathway analysis. Patients attending the HTLV-1 clinic at St Mary’s hospital in London, UK were classified according to their clinical status as asymptomatic HTLV-1 carriers (ACs, n=20), patients with HTLV-1-associated meylopathy (HAM, n=10) or uninfected control subjects (n=9). HTLV-1 proviral load (PVL) can differ among individuals by more than 10-fold and is typically higher in patients with HAM than in ACs, with a 1% PVL cut off generally separating disease from asymptomatic carriage. Thus, ACs were subdivided into AC low PVL (<1% infected PBMCs) and AC high PVL (>1% infected PBMCs). Three ml of blood were drawn into a Tempus tube (Applied Biosystems, Foster City, CA, USA). Total RNA was extracted, globin mRNA depleted and following cRNA generation samples were analysed on HUmanHT12 v3 Illumina BeadChip arrays.

ORGANISM(S): Homo sapiens

SUBMITTER: Charles Bangham

PROVIDER: E-GEOD-29312 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an inflammatory neurodegenerative disease that affects motor, urinary, intestinal, and sensory functions. Typically, HAM/TSP is slowly progressive, but it may vary from limited motor disability after decades (very slow progression) to loss of motor function in a few years from disease onset (rapid). In this study, we aimed to identify prognostic biomarkers for HAM/TSP to support patient management. Thus, proteomic analysis of the cerebrospinal fluid (CSF) was performed with samples from HTLV-1 asymptomatic carriers (AC) (n=13) and HAM/TSP patients (n=21) with rapid, typical, and very slow progression using quantitative label-free liquid chromatography/tandem mass spectrometry. Enrichment analyses were also carried out to identify key biological processes associated with distinct neurological conditions in HTLV-1 infection. Candidate biomarkers were validated by ELISA in paired CSF and serum samples, and samples from HTLV-1-seronegative individuals (n=9) were used as controls. CSF analysis identified 602 proteins. Leukocyte/cell activation, immune response processes and neurodegeneration pathways were enriched in rapid progressors. Conversely, HTLV-1 AC and HAM/TSP patients with typical and very slow progression had enriched processes for nervous system development. Differential expression analysis showed that soluble vascular cell adhesion molecule 1 (sVCAM-1), chitotriosidase 1 (CHIT1), and cathepsin C (CTSC) were upregulated in HAM/TSP. However, only CHIT1 was significantly elevated after validation, particularly in HAM/TSP rapid progressors. In contrast, none of these biomarkers were altered in serum. Additionally, CSF CHIT1 levels in HAM/TSP patients positively correlated with the speed of HAM/TSP progression, defined as points in the IPEC-2 HAM/TSP disability scale per year of disease, and with CSF levels of phosphorylated neurofilament heavy chain, neopterin, CXCL5, CXCL10, and CXCL11. In conclusion, higher CSF levels of CHIT1 were associated with HAM/TSP rapid progression and correlated with other biomarkers of neuroinflammation and neurodegeneration. Therefore, we propose CHIT1 as a surrogate CSF biomarker to identify HAM/TSP patients with a worse prognosis.

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Genome-wide analysis of gene expression profiles in individuals infected with the Human T-Lymphotropic virus Type 1 (HTLV-1) - train set

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