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1.
Brain Res ; 1574: 84-95, 2014 Jul 29.
Article in English | MEDLINE | ID: mdl-24928618

ABSTRACT

Toll-like receptors (TLRs) are known to be activated in Central Nervous System (CNS) viral infections and are recognized to be a critical component in innate immunity. Several reports state a role for particular TLRs in various CNS viral infections. However, excessive TLR activation was previously reported by us in correlation with a pathogenic, rather than a protective, outcome, in a model of SIV encephalitis. Here we aimed at understanding the impact of TLR-mediated pathways by evaluating the early course of pathogenesis in the total absence of TLR signaling during CNS viral infections. We utilized a mouse model of sublethal West Nile virus (WNV) infection. WNV is an emerging neurotropic flavivirus, and a significant global cause of viral encephalitis. The virus was peripherally injected into animals that simultaneously lacked two key adapter molecules of TLR signaling, MyD88 and TRIF. On day 2 pi (post infection), MyD88/Trif-/- mice showed an increased susceptibility to WNV infection, and revealed an impairment in innate immune cytokines, when compared to wild type mice (WT). By day 6 pi, there was an increase in viral burden and robust expression of inflammatory cytokines as well as higher cell infiltration into the CNS in MyD88/Trif-/-, when compared to infected WT. A drastic increase in microglia activation, astrogliosis, and inflammatory trafficking were also observed on day 6 pi in MyD88/Trif-/-. Our observations show a protective role for TLR signaling pathways in preventing lethal encephalitis at early stages of WNV infection.


Subject(s)
Brain/physiopathology , Toll-Like Receptors/metabolism , West Nile Fever/physiopathology , Adaptor Proteins, Vesicular Transport/genetics , Adaptor Proteins, Vesicular Transport/metabolism , Animals , Cell Line , Cricetinae , Disease Progression , Male , Membrane Glycoproteins/genetics , Membrane Glycoproteins/metabolism , Mice, Inbred C57BL , Mice, Knockout , Myeloid Differentiation Factor 88/genetics , Myeloid Differentiation Factor 88/metabolism , RNA, Viral/metabolism , Signal Transduction , Survival Analysis , Toll-Like Receptor 3/genetics , Toll-Like Receptor 3/metabolism , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism , Toll-Like Receptor 7/genetics , Toll-Like Receptor 7/metabolism , Toll-Like Receptor 9/genetics , Toll-Like Receptor 9/metabolism , Toll-Like Receptors/genetics , West Nile virus/genetics
2.
Blood ; 112(6): 2411-20, 2008 Sep 15.
Article in English | MEDLINE | ID: mdl-18502825

ABSTRACT

Despite abundant activated virus-specific cytotoxic T lymphocytes (CTLs), patients with human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) showed a significantly higher frequency of infected T cells than did healthy virus carriers (HVCs). Here, we demonstrate that at a given proviral load, the frequency of CD8(+) T cells that are negative for specific costimulatory molecules was significantly higher in HAM/TSP than in age-matched HVCs and uninfected healthy controls (HCs), whereas the frequency of intracellular perforin-positive CD8(+) T cells was significantly lower in both HAM/TSP and HVCs than in HCs. An inverse correlation between HTLV-1 proviral load (PVL) and percent perforin-positive CD8(+) T cells were observed only in disease-protective allele HLA-A*02-positive HVCs, but not in HAM/TSP patients, whether HLA-A*02 positive or negative, nor in HLA-A*02-negative HVCs. Significantly lower perforin expression was observed in HTLV-1-specific than in cytomegalovirus-specific CD8(+) T cells. Majority of HTLV-1-specific CD8(+) T cells in HVCs showed a CD28(-)CD27(+) phenotype, whereas HAM/TSP showed a CD28(-)CD27(-) phenotype. HTLV-1-specific CD8(+) T cells from HAM/TSP patients showed significantly lower degranulation than HVCs by CD107a mobilization assay. These findings suggest that an impaired function of HTLV-1-specific CTLs is associated with failing antiviral control and disease HAM/TSP.


Subject(s)
CD8-Positive T-Lymphocytes/virology , Human T-lymphotropic virus 1/pathogenicity , Paraparesis, Tropical Spastic/immunology , CD8-Positive T-Lymphocytes/pathology , HLA-A2 Antigen/analysis , HTLV-I Infections , Humans , Immunophenotyping , Paraparesis, Tropical Spastic/etiology , Perforin/analysis , T-Cell Antigen Receptor Specificity , T-Lymphocytes, Cytotoxic/pathology , T-Lymphocytes, Cytotoxic/virology , Viral Load
3.
J Neurovirol ; 12(3): 171-7, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16877298

ABSTRACT

The authors have previously developed a logistic regression equation to predict the odds that a human T-cell lymphotropic virus type 1 (HTLV-1)-infected individual of specified genotype, age, and provirus load has HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in southern Japan. This study evaluated whether this equation is useful predictor for monitoring asymptomatic HTLV-1-seropositive carriers (HCs) in the same population. The authors genotyped 181 HCs for each HAM/TSP-associated gene (tumor necrosis factor [TNF]-alpha-863A/C, stromal cell-derived factor 1 (SDF-1) +801G/A, human leukocyte antigen [HLA]-A*02, HLA-Cw*08, HTLV-1 tax subgroup) and measured HTLV-1 provirus load in peripheral blood mononuclear cells using real-time polymerase chain reaction (PCR). Finally, the odds of HAM/TSP for each subject were calculated by using the equation and compared the results with clinical symptoms and laboratory findings. Although no clear difference was seen between the odds of HAM/TSP and either sex, family history of HAM/TSP or adult T-cell lenkemia (ATL), history of blood transfusion, it was found that brisk patellar deep tendon reflexes, which suggest latent central nervous system compromise, and flower cell-like abnormal lymphocytes, which is the morphological characteristic of ATL cells, were associated with a higher odds of HAM/TSP. The best-fit logistic regression equation may be useful for detecting subclinical abnormalities in HCs in southern Japan.


Subject(s)
Carrier State/epidemiology , Human T-lymphotropic virus 1 , Paraparesis, Tropical Spastic/epidemiology , Paraparesis, Tropical Spastic/genetics , Adult , Age Distribution , Chemokine CXCL12 , Chemokines, CXC/genetics , Female , Genetic Predisposition to Disease/epidemiology , Genotype , HLA-A Antigens/genetics , HLA-C Antigens/genetics , Humans , Japan/epidemiology , Logistic Models , Male , Middle Aged , Neurologic Examination , Odds Ratio , Paraparesis, Tropical Spastic/diagnosis , Predictive Value of Tests , Proviruses , ROC Curve , Tumor Necrosis Factor-alpha/genetics , Viral Load
4.
Am J Med Genet B Neuropsychiatr Genet ; 141B(4): 383-6, 2006 Jun 05.
Article in English | MEDLINE | ID: mdl-16583435

ABSTRACT

AKT-glycogen synthase kinase 3beta (GSK3beta) signaling is a target of lithium and has been implicated in the pathogenesis of mood disorders and schizophrenia. AKT1 protein level is decreased in the peripheral lymphocytes and brains of schizophrenic patients. The SNP2/3/4 TCG haplotype of AKT1 was associated with schizophrenia in patients with Northern European origin. In the present study, we genotyped five single nucleotide polymorphisms (SNP1-5) of AKT1 gene according to the original study in Iranians comprising of 321 schizophrenic patients and 383 controls, all residing in Mashhad city, Northeastern Iran. Haplotype analysis showed that the frequency of a five-SNP haplotype (AGCAG) was significantly higher in schizophrenic patients (0.068) than that of controls (0.034) (P = 0.03 after Bonferroni correction, OR = 2.04, CI = 1.2-3.4). In stratified analysis by schizophrenia subtypes, the frequency of the same haplotype was significantly higher in disorganized subtype (n = 78, frequency of haplotype=0.081) when compared with normal controls (P = 0.04 after Bonferroni correction, OR = 2.59, CI = 1.3-5.2). Our findings did not confirm the association of AKT1 SNP2/3/4 TCG haplotype with the risk of schizophrenia as reported in the original study but showed the evidence of association with a different haplotype, AKT1 five-SNP AGCAG haplotype, with the risk of schizophrenia in Iranian population.


Subject(s)
Haplotypes , Proto-Oncogene Proteins c-akt/genetics , Schizophrenia/genetics , Alleles , Gene Frequency , Genotype , Humans , Iran , Linkage Disequilibrium , Polymorphism, Single Nucleotide , Risk Factors
5.
J Neurol Sci ; 246(1-2): 37-43, 2006 Jul 15.
Article in English | MEDLINE | ID: mdl-16545396

ABSTRACT

Human T-cell lymphotropic virus type-1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is chronic inflammatory disease of the spinal cord characterized by perivascular lymphocytic cuffing and parenchymal lymphocytic infiltration. In this study using flow cytometry, we have investigated the T-cell receptor (TCR) Vbeta repertoire of peripheral blood T lymphocytes in 8 HAM/TSP patients, 10 HTLV-1 infected healthy carriers, and 11 uninfected healthy controls to determine if there is a biased usage of TCR Vbeta. We found that TCR Vbeta7.2 was under-utilized and Vbeta12 was over-utilized in CD4+ T cells of HTLV-1 infected individuals compared with healthy uninfected controls, whereas there were no such differences in CD8+ T cells. Comparison of Vbeta repertoire changes before and after interferon-alpha (IFN-alpha) treatment for HAM/TSP revealed that one out of five patients showed dramatic decrease of specific Vbeta in CD8+ T cells. Our results suggest that dominant Vbeta subpopulations in CD4+ T cells evolved associated with chronic HTLV-1 infection, and IFN-alpha treatment for HAM/TSP does not induce a specific pattern of TCR Vbeta changes.


Subject(s)
Antiviral Agents/therapeutic use , HTLV-I Infections/drug therapy , HTLV-I Infections/metabolism , Interferon-alpha/therapeutic use , Paraparesis, Tropical Spastic/drug therapy , Paraparesis, Tropical Spastic/metabolism , Receptors, Antigen, T-Cell, alpha-beta/genetics , Receptors, Antigen, T-Cell, alpha-beta/metabolism , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/metabolism , Flow Cytometry , Humans , Neurologic Examination , Phenotype
6.
J Neurol Sci ; 232(1-2): 29-35, 2005 May 15.
Article in English | MEDLINE | ID: mdl-15850579

ABSTRACT

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is one outcome of human T-cell lymphotropic virus type-1 (HTLV-1) infection. It remains unknown why the majority of infected people remain healthy, whereas only approximately 2-3% of infected individuals develop the disease. The active form of vitamin D has immunomodulatory effects, and allelic variants of the vitamin D receptor (VDR) appear to be associated with differential susceptibility to several infectious diseases. To investigate whether VDR single nucleotide polymorphisms (SNPs) are associated with the development of HAM/TSP, we studied four VDR SNPs in a group of 207 HAM/TSP patients and 224 asymptomatic HTLV-1 seropositive carriers (HCs) in Kagoshima, Japan, by using PCR-RFLP analysis. We found that ApaI polymorphism of VDR is associated with the risk of HAM/TSP, although this polymorphism did not affect the provirus load of HTLV-1 in either HAM/TSP patients or HCs.


Subject(s)
HTLV-I Infections/complications , Paraparesis, Tropical Spastic/etiology , Paraparesis, Tropical Spastic/genetics , Receptors, Calcitriol/genetics , Adult , Alleles , DNA/metabolism , Deoxyribonucleases, Type II Site-Specific/genetics , Female , Genotype , Heterozygote , Humans , Linkage Disequilibrium , Male , Middle Aged , Monocytes/metabolism , Monocytes/pathology , Neopterin/cerebrospinal fluid , Polymorphism, Genetic , Reverse Transcriptase Polymerase Chain Reaction , Sex Characteristics , Viral Load
7.
J Gen Virol ; 86(Pt 3): 773-781, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15722539

ABSTRACT

Human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurological disease observed only in 1-2 % of infected individuals. HTLV-1 provirus load, certain HLA alleles and HTLV-1 tax subgroups are reported to be associated with different levels of risk for HAM/TSP in Kagoshima, Japan. Here, it was determined whether these risk factors were also valid for HTLV-1-infected individuals in Mashhad in northeastern Iran, another region of endemic HTLV-1 infection. In Iranian HTLV-1-infected individuals (n=132, 58 HAM/TSP patients and 74 seropositive asymptomatic carriers), although HLA-DRB1*0101 was associated with disease susceptibility in the absence of HLA-A*02 (P=0.038; odds ratio=2.71) as observed in Kagoshima, HLA-A*02 and HLA-Cw*08 had no effect on either the risk of developing HAM/TSP or HTLV-1 provirus load. All Iranian subjects possessed tax subgroup A sequences, and the protective effects of HLA-A*02 were observed only in Kagoshima subjects with tax subgroup B but not in those with tax subgroup A. Both the prevalence of HTLV-1 subgroups and the host genetic background may explain the different risks levels for HAM/TSP development in these two populations.


Subject(s)
Human T-lymphotropic virus 1/genetics , Paraparesis, Tropical Spastic/genetics , Paraparesis, Tropical Spastic/immunology , Genetic Predisposition to Disease , HLA-A Antigens/genetics , Human T-lymphotropic virus 1/immunology , Humans , Iran , Japan , Paraparesis, Tropical Spastic/etiology , Paraparesis, Tropical Spastic/virology , Risk Factors
8.
J Neuroimmunol ; 156(1-2): 188-94, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15465610

ABSTRACT

Matrix metalloproteinase-9 (MMP-9) has been reported to be expressed in various inflammatory disorders including human T cell lymphotropic virus type I (HTLV-I) associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-I-infected T-cells expressed high levels of MMP-9 via viral transactivator Tax mediated activation of the MMP-9 promoter. To investigate whether the d(CA) repeat polymorphism in MMP-9 promoter affects the risk of developing HAM/TSP, we compared the allele frequencies between 200 HAM/TSP patients and 200 HTLV-I seropositive asymptomatic carriers (HCs). The longer d(CA) repeat alleles of MMP-9 promoter, which was associated with higher Tax-mediated transcriptional activity, was more frequently observed in HAM/TSP patients than HCs (p<0.01 by Mann-Whitney U-test). The length alteration of this d(CA) repeat in the MMP-9 promoter may cause phenotypic differences among HTLV-I infected infiltrating cells and may thereby be in part responsible for the development of HAM/TSP.


Subject(s)
Dinucleotide Repeats/genetics , Gene Products, tax/physiology , Human T-lymphotropic virus 1/physiology , Matrix Metalloproteinase 9/genetics , Paraparesis, Tropical Spastic/genetics , Polymorphism, Genetic , Promoter Regions, Genetic , Adult , Humans , Jurkat Cells , Male , Middle Aged , Paraparesis, Tropical Spastic/enzymology , Paraparesis, Tropical Spastic/virology , Risk Factors
9.
J Infect Dis ; 190(7): 1279-85, 2004 Oct 01.
Article in English | MEDLINE | ID: mdl-15346339

ABSTRACT

To investigate non-human leukocyte antigen candidate genes that influence the outcome of human T cell lymphotropic virus (HTLV) type I infection, we analyzed 6 single-nucleotide polymorphisms in the interleukin (IL)-10 promoter region in 280 patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and 255 HTLV-I-seropositive asymptomatic carriers from an area where HTLV-I is endemic. The IL-10 -592 A allele, which shows lower HTLV-I Tax-induced transcriptional activity than the C allele in the Jurkat T cell line, was associated with a >2-fold reduction in the odds of developing HAM/TSP (P=.011; odds ratio [OR], 0.50 [95% confidence interval, 0.30-0.86]) by reducing the provirus load in the whole cohort (P=.009, analysis of variance). Given the OR and the observed frequency of IL-10 -592 A, we demonstrate that this allele prevents approximately 44.7% (standard deviation, +/-13.1%) of potential cases of HAM/TSP, which indicates that it defines one component of the genetic susceptibility to HAM/TSP in the cohort.


Subject(s)
Interleukin-10/genetics , Paraparesis, Tropical Spastic/etiology , Polymorphism, Single Nucleotide , Promoter Regions, Genetic , Proviruses/isolation & purification , Alleles , Gene Products, tax/physiology , Human T-lymphotropic virus 1/genetics , Paraparesis, Tropical Spastic/genetics , Risk , Viral Load
10.
J Neurol Sci ; 219(1-2): 157-61, 2004 Apr 15.
Article in English | MEDLINE | ID: mdl-15050452

ABSTRACT

HTLV-I- associated myelopathy/tropical spastic paraparesis (HAM/TSP) is one outcome of human T-cell lymphotropic virus type I (HTLV-I) infection. It remains unknown why the majority of infected people remain healthy whereas only approximately 2-3% of infected individuals develop the disease. Recently, it has been reported that increased plasma concentrations of VEGF were significantly related to high ATL cell infiltration, and the viral transactivator Tax activates the VEGF promoter, linking the induction of angiogenesis to viral gene expression. To investigate whether VEGF promoter -634C/G single nucleotide polymorphism (SNP) and serum concentration of VEGF are associated with the development of HAM/TSP, we studied a group of 202 HAM/TSP patients, 202 asymptomatic HTLV-I seropositive carriers (HCs) and 108 seronegative healthy controls (NCs) in Kagoshima, Japan by using PCR-RFLP analysis. The serum concentration of VEGF was also compared among patients with HAM/TSP, ATL, HCs as well as with NCs. Our results indicate that both VEGF gene polymorphism and serum VEGF levels are not specifically associated with the risk of HAM/TSP in our cohort.


Subject(s)
Human T-lymphotropic virus 1/isolation & purification , Paraparesis, Tropical Spastic/blood , Paraparesis, Tropical Spastic/genetics , Vascular Endothelial Growth Factor A/blood , Vascular Endothelial Growth Factor A/genetics , 5' Untranslated Regions/genetics , Antibodies, Viral/blood , Carrier State , Genetic Predisposition to Disease , Human T-lymphotropic virus 1/immunology , Humans , Paraparesis, Tropical Spastic/virology , Polymorphism, Single Nucleotide , Promoter Regions, Genetic/genetics , Proviruses , Viral Load
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