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

胃肠道线虫继续感染人类和动物，对食品安全和全球粮食保障造成重大社会经济后果和影响。这些感染对牲畜生产产生不利影响，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，需要确定保护性抗原并更清楚地了解保护性免疫机制。基于纯化或重组蛋白的兽医疫苗仅具有部分保护作用，无法诱导灭菌免疫，对驱虫药的耐药性正在迅速出现。小鼠病原菌多回螺杆菌（Hpb）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。与具有重要兽医意义的寄生虫类似，Hpb通过口腔-粪便途径传播，感染完全是肠道性的。尽管诱导Th2免疫应答，Hpb感染在C57BL/6 （B6）小鼠和其他近交小鼠品系中是慢性的，并诱导一个强大的调节网络，包括髓源性抑制细胞（MDSC）、调节性T细胞（Tregs）和细胞因子IL-10和tgf - β。胃肠道线虫释放的排泄-分泌（ES）产物（蛋白质、代谢物和mirna）具有免疫调节作用，被认为是重要的候选疫苗和自身免疫性疾病和炎症性疾病的新疗法。小鼠IL-4长效制剂：抗小鼠IL-4单克隆抗体复合物（IL-4C）对感染hbs的小鼠可迅速减少产卵量，减轻成虫负担，并预防慢性感染，但其保护机制尚不清楚。我们提出研究假设，IL-4C给药Hpb感染小鼠增强Th2免疫，降低MDSC和Tregs的扩张和功能，抑制Hpb保护性免疫。我们的具体目标是确定：1)IL-4C处理对消除原发性Hpb感染能力不同的B6和BALB/c小鼠、对Hpb感染易感性过高的irf8缺陷小鼠和外交种CD-1小鼠的成虫负荷和产卵量的影响，以及IL-4C处理是否诱导绝育免疫；2) IL-4C治疗保护作用的免疫机制；3) IL-4C能否作为佐剂提高hpb源性抗原的疫苗效力；4)如果IL-4C与低剂量驱虫药联合治疗以规避耐药性，是否有用。总之，我们的研究将为胃肠道线虫的保护性免疫机制提供更深入的见解，并为开发用于兽医和人类的有效疫苗和新型免疫疗法提供重要信息，以对抗这些无处不在的寄生虫。

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.