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细胞淋巴细胞病毒1型（HTLV-1）感染了全球2000万个人，是HTLV-1相关的骨髓病/热带痉挛性paraparaparaparapareases（HAM/TSP）的因果药。巴西萨尔瓦多-BA的HTLV-1感染率最高。在过去的十年中，随着跨学科团队的参与并与NIH研究人员和康奈尔大学的教职员工合作，我们表征了HTLV-1携带者和HAM/TSP患者的免疫反应，并确定了免疫变化的基础，这些变化会增加HTLV-1感染的htlv-1感染性强大强大型强生菌病的易感性。最近，在NIH授予的R03“免疫反应和疾病表达”的支持下，我们记录了HTLV-1载体在HTLV-1载体中比在静脉控制控制中更高。此外，我们描述了不符合HAM/TSP标准的个体中HTLV-1相关的神经源性膀胱病例，并表明该迹象可能是HAM/TSP的早期表现。目前的提案，标题为与HTLV-1感染相关的疾病表达中的免疫反应，病毒因素和蠕虫感染，扩展了我们以前的研究，以确定：1）HTLV-1感染的自然病史； 2）与疾病表达相关的宿主免疫和病毒因素； 3）蠕虫在免疫反应和HTLV-1感染的临床结果中的影响。使用500个无症状HTLV-1载体的队列，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的恶化。在患有和没有蠕虫感染的患者中，还将比较这些结果。免疫反应和病毒因子在疾病表达中的影响将在三组患者的横断面研究中确定：1）与HTLV-1有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。我们将确定促炎性细胞因子的水平（TNF-，IFN-，IL-17），趋化因子，吸引T细胞到炎症位点（CXCL9，CXCL10），表达IFN和TNF-和TNF-和TNF-和TNF的细胞的CD8 T细胞的频率下降，这些因子和细胞和细胞下调了免疫响应的降低免疫学反应（IL-100，IL-10，IL-27）。将测量病毒载荷，并将病毒DNA存储在未来的研究中，以评估可能与HAM/TSP相关的病毒多态性。公共卫生相关性：关于与HTLV-1相关的临床表现知之甚少，由于只有5％的HTLV-1感染者发展出骨髓病（HAM/TSP），因此HTLV-1被认为是低发病率感染。在这项研究中，评估了前瞻性的500个HTLV-1感染受试者的队列，我们​​将有机会描述HTLV-1感染的自然历史的各个方面，并表明与HTLV-1相关的临床和神经系统表现形式发生在很大比例的感染受试者中。此外，由于在萨尔瓦多 - 巴伊亚（Salvador-Bahia）是蠕虫的特有，并且已广泛表明，蠕虫可以减弱慢性炎症性和自身免疫性疾病的临床表现，我们将确定蠕虫感染对与HTLV-1东北巴西相关的临床表现的影响。此外，我们打算确定免疫反应与病毒因子与HTLV-1感染中疾病表达之间的相关性。这项研究将使我们在疾病的早期阶段鉴定神经系统表现，而潜在的干预措施可以防止神经系统损害并改善神经功能的恢复。