Systems Biology Approaches Reveal a Specific Interferon-Inducible Signature in HTLV-1 Associated Myelopathy

PLoS Pathogens

Jason A. Skinner¹  Damien Chaussabel¹  Matthew P. Berry¹  Jacques Banchereau²  Sonja Tattermusch³  Graham P. Taylor⁴  Anne O'Garra⁵  Charles R. M. Bangham⁵  Finlay W. McNab⁶ 

[1] Baylor Institute for Immunology Research-ANRS Center for Human Vaccines, INSERM U8996, Dallas, Texas, United States of America;Benaroya Research Institute, Seattle, Washington, United States of America;Department of Immunology, Imperial College London, London, United Kingdom;Department of Respiratory Medicine, St Mary's Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom;Division of Immunoregulation, Medical Research Council National Institute for Medical Research, London, United Kingdom;Inflammation and Virology DTA, Hoffman-La Roche Inc, Nutley, New Jersey, United States of America

关键词: HTLV-1;    Gene expression;    Blood;    DNA transcription;    T cells;    Flow cytometry;    Interferons;    Multiple sclerosis;   

DOI  :  10.1371/journal.ppat.1002480

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus that persists lifelong in the host. In ∼4% of infected people, HTLV-1 causes a chronic disabling neuroinflammatory disease known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The pathogenesis of HAM/TSP is unknown and treatment remains ineffective. We used gene expression microarrays followed by flow cytometric and functional assays to investigate global changes in blood transcriptional profiles of HTLV-1-infected and seronegative individuals. We found that perturbations of the p53 signaling pathway were a hallmark of HTLV-1 infection. In contrast, a subset of interferon (IFN)-stimulated genes was over-expressed in patients with HAM/TSP but not in asymptomatic HTLV-1 carriers or patients with the clinically similar disease multiple sclerosis. The IFN-inducible signature was present in all circulating leukocytes and its intensity correlated with the clinical severity of HAM/TSP. Leukocytes from patients with HAM/TSP were primed to respond strongly to stimulation with exogenous IFN. However, while type I IFN suppressed expression of the HTLV-1 structural protein Gag it failed to suppress the highly immunogenic viral transcriptional transactivator Tax. We conclude that over-expression of a subset of IFN-stimulated genes in chronic HTLV-1 infection does not constitute an efficient host response but instead contributes to the development of HAM/TSP.

【 授权许可】

CC BY