Immunological response, Viral Factors and Helminth Infections in Disease Expressi

描述（由申请人提供）：人类T细胞嗜淋巴病毒1型（HTLV-1）感染全球2000万人，是HTLV-1相关脊髓病/热带痉挛性旁瘫（HAM/TSP）的病因。巴西萨尔瓦多-巴是该国HTLV-1感染流行率最高的国家。在过去的10年里，在一个多学科团队的参与下，与美国国立卫生研究院的研究人员和康奈尔大学的教师合作，我们对HTLV-1携带者和HAM/TSP患者的免疫反应进行了表征，并确定了增加HTLV-1感染者对播散性类圆线虫病易感性的免疫变化的基础。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高于血清阴性对照组。此外，我们在不符合HAM/TSP标准的个体中描述了htlv -1相关的神经源性膀胱病例，并表明该体征可能是HAM/TSP的早期表现。本论文题为《HTLV-1感染相关疾病表达中的免疫反应、病毒因子和蠕虫感染》，扩展了我们之前的研究，以确定：1)HTLV-1感染的自然历史；2)与疾病表达相关的宿主免疫和病毒因素；3)寄生虫对HTLV-1感染免疫反应及临床转归的影响。使用500名无症状HTLV-1携带者的队列，将测量以下临床结果：HTLV-1相关的神经源性膀胱、HAM/TSP和神经系统症状的恶化。这些结果也将在有和没有蠕虫感染的患者中进行比较。免疫反应和病毒因子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)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。我们将测定促炎细胞因子（TNF-, IFN-, IL-17）的水平，吸引T细胞到炎症部位的趋化因子（CXCL9, CXCL10），表达IFN-和TNF-的CD8 T细胞的频率，以及下调免疫反应的细胞因子和细胞（IL-10， IL-27调节性T细胞）的频率。前病毒载量将被测量，病毒DNA将被储存，用于未来的研究，旨在评估可能与HAM/TSP相关的病毒多态性。公共卫生相关性：HTLV-1的临床表现知之甚少，由于只有5%的HTLV-1感染者发展为脊髓病（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感染受试者队列的研究中，我们将有机会描述HTLV-1感染的自然史方面，并表明与HTLV-1相关的临床和神经学表现出现在很大比例的感染受试者中。此外，由于蠕虫是萨尔瓦多-巴伊亚州的地方病，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，我们打算在HTLV-1感染中确定免疫反应和病毒因子与疾病表达之间的关系。这项研究将使我们能够在疾病的早期阶段识别神经系统表现，当潜在的干预措施可能预防神经损伤和改善神经功能恢复时。

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.