Testing DNA Vaccine Against T. cruzi in Large Animal Model (Dogs)

在大型动物模型（狗）中测试克氏锥虫 DNA 疫苗

• 批准号: 7385261
• 负责人: Nisha Jain Garg
• 金额: $ 7.55万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7385261
• 关键词: Adjuvant; Alleles; American; Animal Model; Animals; Antibodies; Antigens; Appendix; Area; Blood; Canis familiaris; Cardiac; Cardiomyopathies; Cause of Death; Cellular Immunity; Cessation of life; Chagas Disease; Clinical; Collaborations; Computer Analysis; DNA; DNA Vaccines; Data; Databases; Development; Disease; End Point; Epitopes; Evaluation; Funding; Future; Genes; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Household; Housing; Human; Immune response; Immunity; Immunization; Immunology; Incidence; Individual; Infection; Insect Vectors; Insecta; Interleukin-12; International Aspects; Knowledge; LY6E gene; Mammals; Methods; Mexico; Modeling; Monitor; Mus; Parasitemia; Parasites; Parasitic Diseases; Personal Satisfaction; Plasmids; Population; Positioning Attribute; Prevalence; Prevention approach; Proteins; Reagent; Recombinant Vaccines; Recombinants; Regulation; Resistance; Resistance to infection; Resources; Risk; Route; Symptoms; Testing; Tissues; Trypanosoma cruzi; Trypanosomiasis; Vaccinated; Vaccination; Vaccines; Veterinarians; animal facility; asparaginase; base; cytokine; disability; disease transmission; enzootic; experience; field study; human disease; immunogenicity; novel; novel vaccines; prophylactic; response; sucking; transmission process; vaccine efficacy; vector; vector control; young adult

SUMMARY The protozoan parasite T. cruzi-induced Chagas disease is the prime cause of death in young adults in endemic areas of the American continent and results in >50,000 deaths, 1 million new cases, and loss of 2.74 million disability-adjusted years per year. Chagas disease is principally a zoonotic disease, in which dogs serve as a principal reservoir host and the blood-sucking triatomine insects are the vectors. Strategies leading to reduction of T. cruzi infection in reservoir host (dogs) and dogs' infectivity to triatomines would interrupt parasite transmission, and human cases of new infection and disease. The overall objective of this project is to test the efficacy of a multi-component DNA vaccine constituted of T. cruzi genes encoding ASP-2, TcG1, TcG2 and TcG4; and cytokine adjuvants (i.e. IL-12- and GM-CSF- expression constructs) in inhibiting parasite development in the reservoir host and the insect vector. T. cruzi genes included in the vaccine cocktail are selected for their potential ability to elicit anti-parasite protective immune responses. IL-12 and GM-CSF are selected as adjuvants for the enhancement and regulation of the protective type 1 immune response. Our hypothesis is that immunization of dogs with DNA vaccines would elicit protective immunity against T. cruzi, and thereby, alleviate the ability of this host to infect the vector and maintain the transmission cycle. We will perform immunological, parasitological, and cardiac functional and anatomo-histopathological analyses to test our hypothesis in two specific aims: Aim 1. To determine whether vaccination with the multi-component vaccine elicits anti- T. cruzi humoral and cellular immunity in the canine host. Aim 2. To determine whether DNA vaccination¿induced immunity provides protection from T. cruzi infection and clinical disease in dogs and reduce dogs' infectivity to triatomines. The proposed studies will establish a novel canine model of vaccination and protection from challenge T. cruzi infection. This will be the first attempt to block transmission of T. cruzi to insect vector through a DNA immunization approach. These studies would provide a basis for future field studies focused on evaluating the usefulness of vaccinating dogs as an effective way to control ezootic and enzoonotic transmission of T. cruzi. Infection by Trypanosoma cruzi causes Chagasic cardiomyopathy in humans. Dogs are the principal reservoir host in maintaing parasite transmission in the triatomine vector and humans. The overall objective of this project is to determine whether vaccination of dogs would reduce the infectivity of dogs to the insect vector, and thereby disrupt the transmission cycle.

概括 原生动物寄生虫T. cruzi诱导的查加斯病是年轻人死亡的主要原因 美国大陆的内在区域，导致> 50,000人死亡，100万例新病例，损失2.74 每年有百万个残疾调整年的年份。查加斯病主要是一种人畜共患病，狗服务 作为主要储层宿主和吸血的三角素绝缘材料是载体。导致的策略 减少储层宿主（狗）和狗的感染triatomines中的克鲁兹感染会中断 寄生虫传播以及新感染和疾病的病例。 该项目的总体目的是测试由多组分DNA疫苗的效率 编码ASP-2，TCG1，TCG2和TCG4的T. cruzi基因；和细胞因子调节器（即IL-12和GM-CSF- 表达构建体）在抑制储层宿主和抑制载体中的寄生虫发育方面。 T. Cruzi 疫苗鸡尾酒中包含的基因的潜在能力引起了抗寄生虫保护 免疫反应。选择IL-12和GM-CSF作为调节器，以增强和调节 保护性1型免疫响应。我们的假设是用DNA疫苗对狗的免疫抑制作用 从T. cruzi发出保护的免疫力，从而减轻了该宿主感染矢量的能力和 保持传输周期。我们将执行免疫学，寄生学和心脏功能以及 Anatomo-Instoparological分析以两个具体目的测试我们的假设： 目的1。确定疫苗与多组分疫苗是否引起抗T. cruzi的体液 犬宿主中的细胞免疫。 目的2。确定DNA疫苗接种是否诱导免疫可提供保护侵害克鲁兹的感染 和狗的临床疾病，并将狗的感染减少到三位生胺上。 拟议的研究将建立一种新型的疫苗接种犬模型，并保护挑战T。 克鲁兹感染。这将是首次通过DNA阻断Cruzi向昆虫向量传播的尝试 免疫方法。这些研究将为未来的现场研究提供基础，专注于评估 疫苗接种狗作为控制T. cruzi的Ezootic和enzoonotic传播的有效方法。克鲁兹锥虫感染引起人类的chagasic心肌病。狗是 主要储层宿主在三层媒介和人类中保持寄生虫传播。 该项目的总体目的是确定狗的疫苗接种是否会减少 狗对绝缘载体的感染，从而破坏了传输周期。