Novel nanoparticular diagnostics for cerebral toxoplasmosis and Chagas in HIV patients living in Latin America

针对生活在拉丁美洲的艾滋病毒患者的脑弓形体病和恰加斯病的新型纳米诊断

• 批准号: 10405524
• 负责人: ROBERT H GILMAN
• 金额: $ 64.52万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-18 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10405524
• 关键词: AIDS/HIV problem; Acute; Affect; Affinity; Algorithms; Anti-Retroviral Agents; Antigen Targeting; Antigens; Applications Grants; Area; Binding; Biological Assay; Blood; Body Fluids; Bolivia; Bolivian; Central Nervous System Infections; Cerebral Toxoplasmosis; Cerebrospinal Fluid; Chagas Disease; Clinical; Country; Cryptococcal Meningitis; Data; Development; Diagnosis; Diagnostic; Diagnostic Procedure; Diagnostic Sensitivity; Diagnostic tests; Disease; Dot Immunoblotting; Dyes; HIV; HIV Infections; HIV Seropositivity; Immobilization; Immunoassay; Immunosuppression; Individual; Infection; Latin America; Life; Lung; Meningeal Tuberculosis; Mycobacterium tuberculosis; Neuraxis; Neurologic; Opportunistic Infections; Pathologic; Pathology; Patients; Persons; Peru; Peruvian; Physicians; Pilot Projects; Population; Procedures; Resource-limited setting; Resources; Risk; Savings; Sensitivity and Specificity; Seroprevalences; Site; South America; South American; Specificity; Spinal Puncture; Symptoms; Syndrome; Techniques; Technology; Testing; Time; Toxoplasma gondii; Toxoplasmosis; Trypanosoma cruzi; Urine; Work; antigen detection; antiretroviral therapy; base; clinical diagnosis; co-infection; cohort; diagnostic assay; effective therapy; infection rate; innovation; lateral flow assay; lipoarabinomannan; low and middle-income countries; nanoparticle; nervous system disorder; neuroAIDS; novel; novel diagnostics; opportunistic pathogen; pathogen; pilot test; preservation; reactivation from latency; toxoplasmic encephalitis; urinary; AIDS/HIV problem; Acute; Affect; Affinity; Algorithms; Anti-Retroviral Agents; Antigen Targeting; Antigens; Applications Grants; Area; Binding; Biological Assay; Blood; Body Fluids; Bolivia; Bolivian; Central Nervous System Infections; Cerebral Toxoplasmosis; Cerebrospinal Fluid; Chagas Disease; Clinical; Country; Cryptococcal Meningitis; Data; Development; Diagnosis; Diagnostic; Diagnostic Procedure; Diagnostic Sensitivity; Diagnostic tests; Disease; Dot Immunoblotting; Dyes; HIV; HIV Infections; HIV Seropositivity; Immobilization; Immunoassay; Immunosuppression; Individual; Infection; Latin America; Life; Lung; Meningeal Tuberculosis; Mycobacterium tuberculosis; Neuraxis; Neurologic; Opportunistic Infections; Pathologic; Pathology; Patients; Persons; Peru; Peruvian; Physicians; Pilot Projects; Population; Procedures; Resource-limited setting; Resources; Risk; Savings; Sensitivity and Specificity; Seroprevalences; Site; South America; South American; Specificity; Spinal Puncture; Symptoms; Syndrome; Techniques; Technology; Testing; Time; Toxoplasma gondii; Toxoplasmosis; Trypanosoma cruzi; Urine; Work; antigen detection; antiretroviral therapy; base; clinical diagnosis; co-infection; cohort; diagnostic assay; effective therapy; infection rate; innovation; lateral flow assay; lipoarabinomannan; low and middle-income countries; nanoparticle; nervous system disorder; neuroAIDS; novel; novel diagnostics; opportunistic pathogen; pathogen; pilot test; preservation; reactivation from latency; toxoplasmic encephalitis; urinary

PROJECT SUMMARY Among the most devastating opportunistic diseases associated with human immunodeficiency virus (HIV) are those that affect the central nervous system (CNS). Their nonspecific presentation makes diagnosis difficult even in the best-resourced settings, and in Low and Middle Income Countries (LMICs), a definitive diagnosis can be all but impossible. In this context, CNS infections such as toxoplasmic encephalitis (TE) and CNS Chagas disease are often treated empirically, which can be fatal when physicians' best guesses are incorrect. Toxoplasma gondii seroprevalence is estimated to be highest in Latin America, but diagnosis in HIV-positive patients is difficult without expensive technologies that are unavailable in resource-poor countries. Similarly, Chagas disease, caused by Trypanosoma cruzi, is a serious opportunistic infection in people living with HIV/AIDS, and is also difficult to diagnose. Finally, tuberculosis meningitis (TBM) is difficult to diagnose and frequently fatal because of the delay in diagnosis. 33% of Peruvians and Bolivians are at risk for the development of TB, when patients are HIV positive they are at risk of TBM. Much of South America, including our study site in Bolivia, is highly endemic for both T. cruzi and T. gondii as well as other common CNS opportunistic pathogens. We propose the development and pilot testing of a novel diagnostic assays and their use in clinical diagnosis of TE and CNS Chagas disease through the following aims: Specific Aim 1: Development of parallel lateral flow assays for TE, TBM, and CNS Chagas. In addition to our already developed dot blot assays for Chagas and TB, we have preliminary data that demonstrates nanoparticles' ability to capture and detect multiple T. gondii antigens. (3-5) With further development, we will be able to transition these individual immunoassays into a simultaneous lateral flow test. Specific Aim 2. To determine the sensitivity and specificity of the nanoparticle diagnostic assays for TE, TBM and CNS Chagas disease in a well-characterized cohort of HIV-infected patients with acute neurological syndromes. We expect that the proportion of neurological syndromes due to toxoplasmosis, TBM, and cryptococcal meningitis will be similar to those in other South American HIV populations. We anticipate, however, that CNS Chagas disease will also cause a substantial proportion of neurological disease in the Bolivian population, which may have been underdiagnosed. This project will help define the clinical spectrum of HIV-associated neurological disease in Latin America and use innovative diagnostic techniques to distinguish between CNS Chagas disease, TBM, TE, and other CNS infections. Where multiple pathogens are endemic and are rapidly fatal, more rapid, sensitive, and specific tests could accelerate the initiation of specific and potentially life-saving therapy.

项目摘要 与人类免疫缺陷病毒（HIV）相关的最具破坏性的机会性疾病之一是 那些影响中枢神经系统（CNS）的人。他们的非特异性表现使诊断甚至很难 在资源最佳的环境以及低收入和中等收入国家（LMIC）中，可以是确定的诊断 几乎不可能。在这种情况下，CNS感染（例如弓形虫脑炎（TE）和CNS Chagas） 疾病通常是经验治疗的，当医生的最佳猜测不正确时，这可能是致命的。 弓形虫弓形血清阳性估计在拉丁美洲估计最高，但在HIV阳性中诊断 如果没有昂贵的技术在资源贫乏的国家中无法获得的昂贵技术，患者就很困难。相似地， 由Cruzi锥虫引起的Chagas病是一种严重的机会感染 艾滋病毒/艾滋病，也很难诊断。最后，结核病脑膜炎（TBM）很难诊断 由于诊断的延迟，经常致命。 33％的秘鲁人和玻利维亚人有发展的风险 结核病，当患者呈HIV阳性时，他们有TBM的风险。南美大部分地区，包括我们的学习网站 在玻利维亚，克鲁齐和贡迪的T. 病原体。我们建议对新型诊断测定法进行开发和试点测试及其在临床中的使用 通过以下目的诊断TE和CNS Chagas疾病： 特定目的1：开发TE，TBM和CNS Chagas的平行侧向流量测定。此外 我们已经开发了chagas和TB的DOT印迹分析，我们有初步数据证明 纳米颗粒捕获和检测多种T. gondii抗原的能力。 （3-5）随着进一步的发展，我们将 能够将这些个体免疫测定转换为同时进行侧向流程测试。 具体目标2。确定纳米颗粒诊断测定的敏感性和特异性， 在急性的艾滋病毒感染人群中，TBM和CNS Chagas病中 神经综合征。我们预计由于弓形虫病TBM而引起的神经系统综合征的比例 并且隐球菌脑膜炎将与其他南美HIV种群相似。我们期望， 但是，CNS Chagas疾病还将引起大量的神经系统疾病 玻利维亚人口，可能被诊断不足。 该项目将有助于定义拉丁美洲和 使用创新的诊断技术来区分CNS Chagas病，TBM，TE和其他CNS 感染。多种病原体是地方性的，并且快速致命，更快，更敏感和特定的测试 可以加速特定和潜在的挽救生命疗法的开始。