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

总结 原生动物寄生虫T.克鲁兹引起的恰加斯病是非洲年轻人死亡的主要原因。 美洲大陆的流行区，并导致> 50，000人死亡，100万新病例和2.74的损失。 残疾调整年。恰加斯病主要是一种人畜共患疾病， 作为主要的储存宿主，吸血锥蝽昆虫是传播媒介。战略导致 减少T。储库宿主（犬）的Cruzi感染和犬对锥蝽的感染性将中断 寄生虫传播和人类新感染和疾病病例。 该项目的总体目标是测试由以下组成的多组分DNA疫苗的效力： T.编码ASP-2、TcG 1、TcG 2和TcG 4的cruzi基因;和细胞因子佐剂（即IL-12-和GM-CSF-）。 表达构建体）在抑制寄生虫在储库宿主和昆虫载体中发育中的作用。T. cruzi 包含在疫苗混合物中的基因是根据它们引发抗寄生虫保护性的潜在能力来选择的。 免疫反应。IL-12和GM-CSF被选择作为佐剂，用于增强和调节免疫调节。 保护性1型免疫反应。我们的假设是，用DNA疫苗免疫狗， 引发针对T. cruzi，从而减轻该宿主感染载体的能力， 保持传输周期。我们将进行免疫学，寄生虫学，和心脏功能， 解剖组织病理学分析，以检验我们的假设在两个具体目标： 目标1。目的：确定多组分疫苗接种是否产生抗T。克氏体液 和细胞免疫的能力。 目标2.为了确定DNA疫苗接种诱导的免疫是否提供对T.克氏锥虫感染 和临床疾病，并降低犬对锥蝽的感染性。 本研究将建立一种新的疫苗接种和保护犬免受攻击T。 克氏感染这将是第一次尝试阻止T。cruzi通过DNA转化为昆虫载体 免疫方法。这些研究将为今后的实地研究提供基础， 给狗接种疫苗是控制T.克鲁兹克氏锥虫感染可引起人类恰格虫性心肌病。狗是 维持锥蝽媒介和人类中寄生虫传播的主要储存宿主。 本项目的总体目标是确定犬只接种疫苗是否会减少 狗对昆虫媒介的感染性，从而破坏传播周期。

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.