Exploiting immunotherapeutic approaches to define protective immune mechanisms to chronic GI nematode infections

胃肠道线虫继续感染人和动物，造成重大社会经济后果，并对食品安全和全球食品安全产生影响。这些感染对畜牧业生产产生不利影响，对受感染宿主的体重增加和受孕率产生负面影响。开发针对寄生虫的疫苗具有挑战性，需要识别保护性抗原并更清楚地了解保护性免疫机制(S)。基于纯化或重组蛋白的兽用疫苗仅具有部分保护作用，无法诱导灭菌免疫，对驱虫药的抗药性正在迅速出现。小鼠多回螺旋体是研究胃肠道线虫感染中宿主-寄生虫相互作用的理想工具。与兽医重要的寄生虫类似，HPB通过口腔-粪便途径传播，感染完全通过肠道。尽管HPB感染可以诱导Th2免疫应答，但在C57BL/6(B6)小鼠和其他近交系小鼠中，HPB感染是慢性的，并诱导出一个强大的调节网络，包括髓系来源的抑制细胞(MDSC)、调节性T细胞(Tregs)以及细胞因子IL-10和转化生长因子-β(TGF-β)。胃肠道线虫分泌的排泄物(ES)产物(蛋白质、代谢物和miRNAs)负责其免疫调节作用，被认为是治疗自身免疫性和炎症性疾病的重要候选疫苗和新疗法。给HPB感染的小鼠注射一种长效的小鼠IL-4：抗鼠IL-4单抗复合体(IL-4C)可迅速减少产卵量，减少成虫负担，并防止慢性感染，但保护机制(S)尚不清楚。我们提出的假设是，给感染HPB的小鼠注射IL-4C可以增强Th2免疫，并降低MDSC和Tregs的扩张和功能，从而抑制对HPB的保护性免疫。我们的具体目标是：1)IL-4C治疗对B6和BALB/c小鼠成虫负担和产卵量的影响，这些小鼠在消除原发HPB感染的能力上存在差异，IRF8缺陷小鼠对HPB感染具有过度易感性，以及异种CD-1小鼠，以及IL-4C治疗是否诱导不孕免疫；2)IL-4C治疗保护作用的免疫机制；3)IL-4C是否可以作为佐剂来提高HPB来源的抗原的疫苗效力；4)IL-4C联合小剂量驱虫药治疗是否有效，以避免耐药。总之，我们的研究将更深入地了解对胃肠道线虫的保护性免疫机制(S)，并为开发有效的兽医用疫苗和新型免疫疗法以及针对这些无处不在的寄生虫的人类提供重要信息。

Gastrointestinal (GI) nematodes continue to infect humans and animals with major socio-economic consequences and impacts on food safety and global food security. These infections adversely affect livestock production with negative effects on weight gain and conception rates in infected hosts. Development of vaccines against parasitic worms is challenging and requires the identification of protective antigens and a clearer understanding of the protective immune mechanism(s). Veterinary vaccines based on purified or recombinant proteins are only partially protective and unable to induce sterilizing immunity, and resistance to anthelmintics is rapidly emerging. The mouse pathogen Heligmosomoides polygyrus bakeri (Hpb) is an ideal tool to study host-parasite interactions in GI nematode infections. Similar to parasitic worms of veterinary importance, Hpb transmission occurs via an oral-fecal route and infection is entirely enteric. Despite inducing a Th2 immune response, Hpb infection is chronic in C57BL/6 (B6) mice and other inbred mouse strains and induces a potent regulatory network including myeloid-derived suppressor cells (MDSC), regulatory T cells (Tregs), and the cytokines IL-10 and TGF-beta. Excretory-secretory (ES) products (proteins, metabolites and miRNAs) released by GI nematodes are responsible for their immunomodulatory effects and considered as important vaccine candidates and novel therapy for autoimmune and inflammatory diseases. Administration of a long acting formulation of murine IL-4:anti-mouse IL-4 monoclonal antibody complexes (IL-4C) to Hpb-infected mice rapidly reduces egg production, decreases adult worm burden, and prevents chronic infection, but the protective mechanism(s) is unknown. We propose to investigate the hypothesis that IL-4C administration to Hpb-infected mice enhances Th2 immunity and decreases the expansion and function of MDSC and Tregs that suppress protective immunity to Hpb. Our specific objectives are to determine: 1) the effects of IL-4C treatment on adult worm burden and egg production in B6 and BALB/c mice that differ in their ability to eliminate primary Hpb infection, IRF8-deficient mice with exaggerated susceptibility to Hpb infection, and out-bred CD-1 mice, and if IL-4C treatment induces sterilizing immunity; 2) the immune mechanisms underlying the protective effect of IL-4C treatment; 3) if IL-4C can be used as an adjuvant to improve the vaccine efficacy of Hpb-derived antigens; and 4) if IL-4C is useful therapeutically in combination with a low dose of anthelmintic drug to circumvent drug resistance. Together, our studies will provide greater insight into the mechanism(s) of protective immunity to GI nematodes and important information for development of effective vaccines and novel immunotherapy for veterinary use as well as for humans against these ubiquitous parasites.