The Host Immune Response to HTLV-1 Infection PDF Download
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Author: Sonja Tattermusch
Publisher:
ISBN:
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Languages : en
Pages :
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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. In this study we aimed to identify patterns in frequencies of peripheral leukocyte populations and blood gene expression profiles of HTLV-1 carriers that suggest new hypotheses as to the mechanisms of HTLV-1 persistence and HAM/TSP pathology. Flow cytometric immunophenotyping of peripheral blood leukocytes revealed abnormal activation and maturation profiles of effector T cells but not antigen-presenting cells. High frequencies of circulating granzyme and perforin-rich CD8+ T cells were associated with an increased probability of HAM/TSP. However, the cytolytic capacity of these T cells is not known as although they accumulated cytolytic proteins, granzyme mRNA levels were down-regulated in patients with HAM/TSP. Furthermore, presence of HAM/TSP was associated with an expansion of CD56-negative NK cells, which are thought to have decreased cytolytic functions. Blood gene expression profiles identified perturbations of the p53 signalling pathway as 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. Based on our findings we hypothesise that impaired NK cell and T cell-mediated immune responses result in high HTLV-1 proviral loads but that the over-expression of a subset of IFN-stimulated genes contributes to the development of HAM/TSP.
Author: Sonja Tattermusch
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Book Description
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. In this study we aimed to identify patterns in frequencies of peripheral leukocyte populations and blood gene expression profiles of HTLV-1 carriers that suggest new hypotheses as to the mechanisms of HTLV-1 persistence and HAM/TSP pathology. Flow cytometric immunophenotyping of peripheral blood leukocytes revealed abnormal activation and maturation profiles of effector T cells but not antigen-presenting cells. High frequencies of circulating granzyme and perforin-rich CD8+ T cells were associated with an increased probability of HAM/TSP. However, the cytolytic capacity of these T cells is not known as although they accumulated cytolytic proteins, granzyme mRNA levels were down-regulated in patients with HAM/TSP. Furthermore, presence of HAM/TSP was associated with an expansion of CD56-negative NK cells, which are thought to have decreased cytolytic functions. Blood gene expression profiles identified perturbations of the p53 signalling pathway as 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. Based on our findings we hypothesise that impaired NK cell and T cell-mediated immune responses result in high HTLV-1 proviral loads but that the over-expression of a subset of IFN-stimulated genes contributes to the development of HAM/TSP.
Author: Sonja Tattermusch
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
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Author: Bryan Cullen
Publisher: Oxford University Press
ISBN: 9780199633821
Category : Gene Expression Regulation.
Languages : en
Pages : 220
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Book Description
The first book to specifically cover the molecular biology of retroviruses - of immense importance since the high profile of HIV. International contributors provide detailed reviews of the latest knowledge. An excellent text for both medical and non-medical researchers, it also serves as an illuminating introduction for scientists active in other areas.
Author: Saifur Rahman
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Author: Roberto S. Accolla
Publisher: Frontiers Media SA
ISBN: 2832527728
Category : Medical
Languages : en
Pages : 248
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Book Description
Author: Michael B. A. Oldstone
Publisher: Springer Science & Business Media
ISBN: 3540307915
Category : Medical
Languages : en
Pages : 166
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Book Description
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Author: National Research Council
Publisher: National Academies Press
ISBN: 0309220424
Category : Science
Languages : en
Pages : 200
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Book Description
For many years, experiments using chimpanzees have been instrumental in advancing scientific knowledge and have led to new medicines to prevent life-threatening and debilitating diseases. However, recent advances in alternate research tools have rendered chimpanzees largely unnecessary as research subjects. The Institute of Medicine, in collaboration with the National Research Council, conducted an in-depth analysis of the scientific necessity for chimpanzees in NIH-funded biomedical and behavioral research. The committee concludes that while the chimpanzee has been a valuable animal model in the past, most current biomedical research use of chimpanzees is not necessary, though noted that it is impossible to predict whether research on emerging or new diseases may necessitate chimpanzees in the future.
Author: Robyn A. Haines
Publisher:
ISBN:
Category :
Languages : en
Pages : 247
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Book Description
Abstract: The complex retrovirus Human T-lymphotropic virus type-1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma and other lymphocyte-mediated inflammatory disorders. In endemic regions, HTLV-1 is primarily spread from mother to child through infected breast milk. The establishment of persistent HTLV-1 infection following the ingestion of infected lymphocytes is determined by the delicate balance between viral spread and the host immune response. The immunopathogenesis of these early events is not completely understood, and advances in this area have been hindered by the lack of an appropriate animal model. This thesis describes a novel rabbit model of HTLV-1 milk-borne infections, and provides data to understand the early immunological and virological events following oral mucosal exposure to HTLV-1. Herein, we performed an extensive examination of the rabbit gut-associated lymphoid tissue. Using two quantitative methods to exam lymphocyte subsets within the major inductive sites our data revealed similarities between rabbits and humans. This information validates this species as a model for mucosal immunology studies following oral exposure to HTLV-1 and establishes reference ranges for future studies. Our data provides important knowledge of the immune response against HTLV-1 infection following oral exposure to infected lymphocytes. We established a protocol for infection via the oral mucosal route using a method that mimics infant exposure to repeated doses of comparable numbers of infected lymphocytes. We further characterized this model of infection through evaluation of humoral and cellular immune responses and viral parameters. We determined that rabbits exposed orally to HTLV-1 infected lymphocytes develop a persistent infection characterized by a delayed and variable humoral immune response similar to infected infants. Rabbits exposed by this route also displayed a variable, decreased and delayed peripheral cellular immune response with lower and variable proviral loads and p19 antigen production from ex vivo cultured peripheral blood mononuclear cells when compared to rabbits infected by the intravenous route. This animal model of HTLV-1 infection was used to study early spatial and temporal events following mucosal viral infection. Our data indicates that oral inoculation with HTLV-1 infected lymphocytes results in systemic virus distribution by four weeks post inoculation. Early viral reservoirs include the spleen, mesenteric lymph node, and gut-associated lymphoid tissues (GALT). Within the GALT, there is quiescent integrated provirus within the effector sites and mesenteric lymph node, and actively replicating virus within the inductive sites and spleen. Collectively, data presented in this thesis indicates that HTLV-1 infection following oral exposure induces a delayed and decreased systemic immune response to viral exposure. Our data indicates that the events associated with development of HTLV-1 persistent infections following milk-borne transmission occur below the level of detection within tissue compartments for the first four weeks following exposure, prior to systemic spread.
Author: R. Ahmed
Publisher: Wiley-Blackwell
ISBN:
Category : Medical
Languages : en
Pages : 754
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Book Description
Persistent Viral Infections Edited by Rafi Ahmed Emory Vaccine Center, Atlanta, USA and Irvin S. Y. Chen UCLA School of Medicine, Los Angeles, USA During the past decade much of our attention has focused on diseases associated with viral persistence. Major breakthroughs in immunology, and the advent of molecular approaches to study pathogenesis have increased our understanding of the complex virus-host interactions that occur during viral persistence. Persistent Viral Infections focuses on: * The pathogenesis and immunology of chronic infections * Animal models that provide, or have the potential to provide, major insights This volume will be essential reading for virologists, immunologists, oncologists and neurologists.
Author: Tomoo Sato
Publisher:
ISBN:
Category : Medicine
Languages : en
Pages :
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Book Description
Host Immune System Abnormalities Among Patients with Human T-Lymphotropic Virus Type 1 (HTLV-1) - Associated Disorders.
