Immunological response, Viral Factors and Helminth Infections in Disease Expressi

疾病表现中的免疫反应、病毒因素和蠕虫感染

• 批准号: 8025942
• 负责人: Edgar M Carvalho
• 金额: $ 7.94万
• 依托单位: FEDERAL UNIVERSITY OF BAHIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-15 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8025942
• 关键词: Attenuated; Autoimmune Process; Award; Brazil; CD8B1 gene; CXCL10 gene; CXCL9 gene; Cells; Chronic; Cities; Clinic; Clinical; Cohort Studies; Collaborations; Country; Cross-Sectional Studies; Development; Disease; Enrollment; Erectile dysfunction; Faculty; Frequencies; Future; Genetic Polymorphism; Helminths; High Prevalence; Human T-lymphotropic virus 1; Immune System Diseases; Immune response; Immunologic Factors; Immunology; Individual; Infection; Inflammatory; Interferons; Interleukin-10; Interleukin-17; Intervention; Joints; Leg; Lymphocyte; Measures; Morbidity - disease rate; Natural History; Nervous System Physiology; Nervous System Trauma; Neurogenic Bladder; Neurologic; Neurologic Manifestations; Numbness; Outcome; Patients; Periodontitis; Phase; Predisposition; Principal Investigator; Production; Recovery; Regulatory T-Lymphocyte; Research Personnel; Risk Factors; Sample Size; Schistosoma mansoni; Services; Sicca Syndrome; Site; Spinal Cord Diseases; Strongyloidiasis; T-Lymphocyte; TNF gene; Tropical Spastic Paraparesis; United States National Institutes of Health; Universities; Viral; Walking; base; chemokine; cohort; cytokine; foot; high risk; improved; multidisciplinary; prevent; programs; progression marker; public health relevance; response; urinary; viral DNA

DESCRIPTION (provided by applicant): The human T cell lymphotropic virus type 1 (HTLV-1) infects 20 million individuals worldwide and is the causal agent of HTLV-1-associated myelopathy/Tropical Spastic Paraparesis (HAM/TSP). Salvador-Ba, Brazil has the highest prevalence of HTLV-1 infection in the country. In the last 10 years, with the participation of a multidisciplinary team and in collaboration with NIH researchers and faculty of Cornell University, we have characterized immunological responses in HTLV-1 carriers and in patients with HAM/TSP and determined the basis of the immunological changes that increase the susceptibility of HTLV-1 infected subjects to development of disseminated strongyloidiasis. More recently, under the support of an R03 "Immunological Response and Disease Expression in HTLV-1" awarded by the NIH, we documented that neurological and joint manifestations, periodontitis, sicca syndrome, urinary manifestations and erectile dysfunction were higher among HTLV-1 carriers than in seronegative controls. Moreover, we described cases of HTLV-1-associated neurogenic bladder among individuals who do not fulfill the criteria for HAM/TSP and showed that this sign could be an early manifestation of HAM/TSP. The present proposal, entitled Immunological response, Viral Factors and Helminth Infections in Disease Expression Associated with HTLV-1 Infection, extends our previous studies to determine: 1) The natural history of HTLV-1 infection; 2) Host immunological and viral factors associated with disease expression; and 3) The influence of helminths in the immune response and in the clinical outcome of HTLV-1 infection. Using a cohort of 500 asymptomatic HTLV-1 carriers, the following clinical outcomes will be measured: neurogenic bladder associated with HTLV-1, HAM/TSP, and worsening of neurological manifestations. These outcomes will also be compared in patients with and without helminth infection. The influence of immunological responses and viral factors in disease expression will be determined in a cross-sectional study with three groups of patients: 1) Patients with neurogenic bladder associated with HTLV-1; 2) Patients with HAM/TSP; and 3) Patients with asymptomatic HTLV-1 infection. We will determine levels of pro-inflammatory cytokines (TNF-, IFN-, IL-17), chemokines that attract T cells to inflammatory sites (CXCL9, CXCL10), the frequency of CD8 T cells expressing IFN- and TNF- and of cytokines and cells that down-modulate immunological response (IL-10, IL-27 regulatory T cells). Proviral load will be measured and viral DNA will be stored for future studies aimed at evaluating viral polymorphisms that could be associated with HAM/TSP. PUBLIC HEALTH RELEVANCE: Very little is known about clinical manifestations associated with HTLV-1, and as only 5% of HTLV-1-infected individuals develop myelopathy (HAM/TSP), HTLV-1 is considered a low morbidity infection. In this study evaluating prospectively a cohort of 500 HTLV-1 infected subjects, we will have the opportunity to describe aspects of the natural history of HTLV-1 infection and to show that clinical and neurological manifestations associated with HTLV-1 occur in a large proportion of infected subjects. Moreover, as helminths are endemic in Salvador-Bahia and it has been widely shown that helminths can attenuate clinical manifestations of chronic inflammatory and auto-immune diseases, we will determine the influence of helminth infection on clinical manifestations related to HTLV-1 Northeastern Brazil. Furthermore, we intend to identify a correlation between immunological response and viral factors with disease expression in HTLV-1 infection. This study will allow us Identify neurological manifestations in an early phase of the disease, when potential interventions may prevent neurological damage and improve recovery of neurological function.

描述（由申请人提供）：人类 T 细胞嗜淋巴细胞病毒 1 型 (HTLV-1) 感染全球 2000 万人，是 HTLV-1 相关脊髓病/热带痉挛性截瘫 (HAM/TSP) 的病原体。巴西萨尔瓦多巴省是该国 HTLV-1 感染率最高的地区。在过去的 10 年里，在多学科团队的参与下，并与 NIH 研究人员和康奈尔大学教师合作，我们描述了 HTLV-1 携带者和 HAM/TSP 患者的免疫反应特征，并确定了免疫学变化的基础增加 HTLV-1 感染者患播散性类圆线虫病的易感性。最近，在 NIH 授予的 R03“HTLV-1 的免疫反应和疾病表达”的支持下，我们记录了 HTLV-1 携带者的神经和关节表现、牙周炎、干燥综合征、泌尿系统表现和勃起功能障碍较高。比血清阴性对照。此外，我们描述了不符合 HAM/TSP 标准的个体中 HTLV-1 相关神经源性膀胱的病例，并表明该体征可能是 HAM/TSP 的早期表现。目前的提案题为“HTLV-1感染相关疾病表达中的免疫反应、病毒因素和蠕虫感染”，扩展了我们之前的研究以确定：1）HTLV-1感染的自然史； 2）与疾病表达相关的宿主免疫和病毒因素； 3) 蠕虫对免疫反应和 HTLV-1 感染临床结果的影响。使用由 500 名无症状 HTLV-1 携带者组成的队列，将测量以下临床结果：与 HTLV-1、HAM/TSP 相关的神经源性膀胱以及神经系统表现恶化。还将在有和没有蠕虫感染的患者中比较这些结果。免疫反应和病毒因素对疾病表达的影响将通过三组患者的横断面研究来确定：1) 与 HTLV-1 相关的神经源性膀胱患者； 2) HAM/TSP患者； 3) 无症状HTLV-1感染患者。我们将确定促炎细胞因子（TNF-、IFN-、IL-17）、吸引 T 细胞到达炎症部位的趋化因子（CXCL9、CXCL10）的水平、表达 IFN- 和 TNF- 的 CD8 T 细胞以及细胞因子的频率以及下调免疫反应的细胞（IL-10、IL-27 调节性 T 细胞）。将测量原病毒载量并储存病毒 DNA，以供未来研究评估可能与 HAM/TSP 相关的病毒多态性。公众健康相关性：人们对与 HTLV-1 相关的临床表现知之甚少，并且由于只有 5% 的 HTLV-1 感染者出现脊髓病 (HAM/TSP)，因此 HTLV-1 被认为是一种低发病率感染。在这项前瞻性评估 500 名 HTLV-1 感染受试者的研究中，我们将有机会描述 HTLV-1 感染自然史的各个方面，并表明与 HTLV-1 相关的临床和神经学表现在很大程度上发生受感染的受试者。此外，由于蠕虫在萨尔瓦多-巴伊亚州流行，并且已广泛表明蠕虫可以减轻慢性炎症和自身免疫性疾病的临床表现，因此我们将确定蠕虫感染对巴西东北部HTLV-1相关临床表现的影响。此外，我们打算确定免疫反应和病毒因素与 HTLV-1 感染中疾病表达之间的相关性。这项研究将使我们能够识别疾病早期阶段的神经系统表现，此时潜在的干预措施可能会预防神经损伤并改善神经功能的恢复。