Mucosal Immune Responses in Hookworm Infection

描述（由申请人提供）：钩虫仍然是发展中国家的主要健康负担，超过10亿人被感染，数亿人患有临床相关病理。未来钩虫病的大量减少可能需要将传统的控制策略与新的方法结合起来，如旨在改善吸血成虫寄生虫引起的临床后遗症的疫苗。如果在合适的动物模型中鉴定和表征保护性免疫应答，疫苗开发将是最有效的。寄生在宿主肠道中的成年吸血钩虫分泌各种蛋白质，已知这些蛋白质可诱导强烈的全身免疫应答。相比之下，附着部位及其周围的粘膜免疫反应没有得到很好的描述。我们假设，成人钩虫驻留在宿主肠道诱导特异性粘膜免疫反应的体液和细胞的车厢，这些反过来又发挥了作用，获得性抵抗钩虫病。我们进一步假设粘膜接种可用于人工诱导对钩虫感染和/或疾病的抗性。 因此，本项目的目的将是表征粘膜免疫反应的抗体，细胞和细胞因子水平的仓鼠模型的锡兰钩虫感染。将使用通过口服途径递送的可溶性钩虫提取物优化粘膜免疫方案。将使用酶联免疫吸附试验和免疫印迹法评价粘膜免疫的免疫原性，并使用贫血、生长和蠕虫负荷的临床测量值评估保护效力。优化的粘膜免疫方案然后将用于评价先前已鉴定并表达为重组蛋白的成虫钩虫抗原的保护效力。这些研究有望进一步加深我们对宿主-寄生虫免疫相互作用的理解，并通过开发新的免疫技术推进钩虫疫苗研究。

DESCRIPTION (provided by the applicant): Hookworms remain a major health burden in the developing world, with over one billion persons infected and hundreds of millions suffering from clinically relevant pathology. Substantial future reduction of hookworm disease will likely require the joining of conventional control strategies with novel approaches such as vaccines aimed at ameliorating the clinical sequelae caused by blood feeding adult parasites. Vaccine development will be most efficient if protective immune responses are identified and characterized in suitable animal models. Adult blood feeding hookworms residing in the host intestine secrete various proteins that are known to induce robust systemic immune responses. By contrast, mucosal immune responses in and around the site of attachment are not as well described. We hypothesize that adult hookworms residing in the host intestine induce specific mucosal immune responses in both the humoral and cellular compartments, and that these in turn play a role in acquired resistance to hookworm disease. We further hypothesize that mucosal vaccination may be employed to artificially induce resistance to hookworm infection and/or disease. Accordingly, the aim of this project will be to characterize mucosal immune responses in the hamster model of Ancylostoma ceylanicum hookworm infection to the antibody, cellular, and cytokine levels. A mucosal immunization protocol will be optimized using soluble hookworm extracts delivered by the oral route. Immunogenicity of mucosal immunization will be evaluated using enzyme-linked immunosorbent assay and immunoblot, and protective efficacy will be assessed using clinical measurements of anemia, growth, and worm burden. The optimized mucosal immunization protocol will then be used to evaluate the protective efficacy of adult hookworm antigens which have been previously identified and expressed as recombinant) proteins. These studies are expected to further our understanding of host-parasite immunological interaction and advance hookworm vaccine research through the development of novel immunization techniques.