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，有超过10亿人感染，数亿人患有与临床相关的病理。钩虫疾病未来的大幅减少可能需要将传统的控制策略与新的方法结合起来，例如旨在改善吸血成虫造成的临床后遗症的疫苗。如果在合适的动物模型中识别和表征保护性免疫反应，疫苗开发将是最有效的。寄生在宿主肠道中的成虫吸血钩虫分泌各种蛋白质，这些蛋白质可诱导强大的全身免疫反应。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。我们假设寄生在宿主肠道的成虫在体液和细胞内都能诱导特异性的粘膜免疫反应，而这些免疫反应又在钩虫疾病的获得性抵抗力中发挥作用。我们进一步推测，粘膜免疫可能被用来人工诱导对钩虫感染和/或疾病的抵抗力。因此，本项目的目的将是表征感染钩虫的仓鼠模型中对抗体、细胞和细胞因子水平的黏膜免疫反应。将使用口服途径提供的可溶钩虫提取物来优化粘膜免疫方案。将使用酶联免疫吸附试验和免疫印迹来评估粘膜免疫的免疫原性，并将使用贫血、生长和蠕虫负担的临床测量来评估保护效果。然后，优化的黏膜免疫方案将用于评估成虫钩虫抗原的保护效果，这些成虫抗原先前已被鉴定并以重组蛋白的形式表达。这些研究有望加深我们对宿主-寄生虫免疫相互作用的了解，并通过开发新的免疫技术来推进钩虫疫苗的研究。

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.