Transmission-blocking live vaccine for Chagas disease

描述（由申请人提供）：迄今为止，人类寄生虫病的疫苗开发尚未取得丰硕奋进，部分原因是这些真核病原体的遗传复杂性以及对有效宿主免疫应答及其使用的免疫逃避机制的了解相对缺乏。 在许多地方，克氏锥虫传播给昆虫--随后传播给人类--几乎完全取决于T。克氏病毒感染了家中的狗或猫。 从逻辑上讲，这意味着给狗和猫接种疫苗，使它们不会感染细菌，这可能是预防人类感染的一种非常有效的工具。 我们建议发展T. cruzi及其作为预防T.从伴侣动物或家畜到昆虫。 利用T.我们将开发无毒力系，选择它们作为外鞭毛体良好生长并转化为感染性亚环锥鞭毛体的能力，在体外感染细胞系，在小鼠体内诱导强T细胞和抗体应答，并最终在用有毒力寄生虫系攻击后防止小鼠和狗中可检测的寄生虫血症的发展。 我们将优化基因敲除（KO）无毒系，通过过表达编码非变异T的低拷贝基因来增强其效力和安全性。cruzi蛋白以及异源蛋白TLR配体从细菌的表达和分泌。 这些修饰有望加速和增强对T.克鲁兹 这种方法的诱人之处在于，伴侣动物的疫苗不必绝对预防感染-只需将这些动物血液中的寄生虫水平保持在昆虫可传播的水平以下。 此外，这种疫苗可以以口服形式提供-使动物的广泛接种变得非常容易。

DESCRIPTION (provided by applicant): Vaccine development for human parasitic diseases has not been a fruitful endeavor to date, in part due to the genetic complexity of these eukaryotic pathogens and the relative lack of understanding of effective host immune responses to, and immune evasion mechanisms used by them. In many sites, the transmission of Trypanosoma cruzi to insects - and subsequently to the people - is nearly totally determined by the presence or absence of T. cruzi infected dogs or cats in the home. Logistically what this means is that vaccination of dogs and cats so that they are not infectious to bugs could be a highly effective tool for the prevention human infections. We propose the development of avirulent lines of T. cruzi and their evaluation as vaccines to prevent the transmission of T. cruzi from companion or livestock animals to insects. Using the specific deletion of T. cruzi genes we will develop avirulent lines, selecting for their ability to grow well as epimastigotes and to convert to infective metacyclic trypomastigotes, to infect cells lines in vitro, to induce strong T cell and antibody responses in vivo in mice and ultimately, to prevent the development of detectable parasitemia in mice and dogs following challenge with virulent parasite lines. We will optimize the gene knockout (KO) avirulent lines to enhance their potency and safety by overexpression of low copy genes encoding non-variant T. cruzi proteins as well as by the expression and secretion of the heterologous protein TLR ligands from bacteria. These modifications are expected to accelerate and potentiate the immune response to T. cruzi. Among the enticing aspects of this approach is that a vaccine for companion animals would not have to absolutely prevent infection - just keep parasite levels in the blood of these animals below the level of transmissibility to insects. Additionally, such a vaccine could be delivered in an oral form - making widespread vaccination of animals quite easy.