Approaches To Immunological Intervention In Schistosomiasis

血吸虫病的免疫干预方法

基本信息

批准号：
8336131
负责人：
Thomas Wynn
金额：
$ 139.63万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8336131
关键词：
Affect Affinity Agreement Area Attenuated Binding Binding Sites CD44 gene Chronic Complex Cytokine Receptors Development Disease Docking Family Fibrosis Goals Granuloma Granulomatous Helminths Human IL2RA gene IgE IgG1 Immune Immune response Immunity Individual Infection Inflammation Interleukin-10 Interleukin-13 Interleukin-4 Interleukin-5 Interleukin-9 Intestines Knockout Mice Lead Liver Liver Fibrosis Lymphocyte Maps Mesentery Methods Modeling Molecular Monoclonal Antibodies Morbidity - disease rate Mus Parasites Pathogenesis Pathology Peptides Portal Hypertension Portal Venous System Praziquantel Process Reporting Research Resistance Resistance development Risk Role Schistosoma Schistosoma mansoni Schistosomiasis Signal Transduction Site Specificity Spleen Structural Models Structure Transgenic Mice Work base chemotherapy cohort cytokine density egg eosinophil immunological intervention interleukin-13 receptor lymph nodes mortality mouse model novel programs protein aminoacid sequence receptor research study response

项目摘要

IIn schistosomiasis, the pathology resulting from chronic infection is predominantly induced by the host immune response to parasite eggs that are laid, in the case of Schistosoma mansoni, in the portal venous system and subsequently trapped in the liver and intestine. The egg induced granulomatous response eventually triggers significant liver fibrosis, which is the primary cause of chronic morbidity and mortality. Our work is focused on elucidating the mechanisms of granulomatous inflammation and fibrosis. Progress was made in the following areas:   1) IL-13 is required for immunity to many helminth infections. IL-13 signals via the type-II IL-4 receptor, a heterodimeric receptor of IL-13Rα1 and IL-4Rα, which is also used by IL-4. IL-13 also binds to IL-13Rα2, but with much higher affinity than the type-II IL-4 receptor. Binding of IL-13 to IL-13Rα2 has been shown to attenuate IL-13 signaling through the type-II IL-4 receptor. However, molecular determinants that dictate the specificity and affinity of mouse IL-13 for the different receptors are largely unknown. Here, we used high-density overlapping peptide arrays, structural modeling, and molecular docking methods to map IL-13 binding sequences on its receptors. Predicted binding sequences on mouse IL-13Rα1 and IL-13Rα2 were in agreement with the reported human IL-13 receptor complex structures and site-directed mutational analysis. Novel structural differences were identified between IL-13 receptors, particularly at the IL-13 binding interface. Notably, additional binding sites were observed for IL-13 on IL-13Rα2. In addition, the identification of peptide sequences that are unique to IL-13Rα1 allowed us to generate a monoclonal antibody that selectively binds IL-13Rα1. Thus, high-density peptide arrays combined with molecular docking studies provide a novel, rapid, and reliable method to map cytokine-receptor interactions that may be used to generate signaling and decoy receptor-specific antagonists that could be used to block schistosomiasis-induced liver fibrosis. 2) Despite effective chemotherapy to treat schistosome infections, re-infection rates are extremely high. Resistance to reinfection can develop, however it typically takes several years following numerous rounds of treatment and re-infection, and often develops in only a small cohort of individuals. Using a well-established and highly permissive mouse model, we investigated whether immunoregulatory mechanisms influence the development of resistance. Following Praziquantel (PZQ) treatment of S. mansoni infected mice we observed a significant and mixed anti-worm response, characterized by Th1, Th2 and Th17 responses. Despite the elevated anti-worm response in PBMC's, liver, spleen and mesenteric lymph nodes, this did not confer any protection from a secondary challenge infection. Because a significant increase in IL-10-producing CD4+CD44+CD25+GITR+ lymphocytes was observed, we hypothesised that IL-10 was obstructing the development of resistance. Blockade of IL-10 combined with PZQ treatment afforded a greater than 50% reduction in parasite establishment during reinfection, compared to PZQ treatment alone, indicating that IL-10 obstructs the development of acquired resistance. Markedly enhanced Th1, Th2 and Th17 responses, worm-specific IgG1, IgG2b and IgE and circulating eosinophils characterized the protection. This study demonstrates that blocking IL-10 signalling during PZQ treatment can facilitate the development of protective immunity and provide a highly effective strategy to protect against reinfection with S. mansoni.

IIN血吸虫病，慢性感染引起的病理主要是由宿主对寄生虫卵的免疫反应诱导的，而在门静脉静脉系统中，寄生的寄生虫卵，随后被困在肝脏和纯料中。卵引起的肉芽肿反应最终会触发明显的肝纤维化，这是慢性发病率和死亡率的主要原因。我们的工作重点是阐明肉芽肿性炎症和纤维化的机制。在以下领域取得了进展：   1）IL-13是对许多蠕虫感染的免疫所必需的。 IL-13通过IL-1型IL-4受体（IL-13Rα1和IL-4Rα的异二聚体受体）通过IL-4受体进行了IL-13信号，IL-4也使用IL-4。 IL-13还与IL-13Rα2结合，但与II II II IL-4受体的亲和力高得多。 IL-13与IL-13Rα2的结合已证明可以通过II II II IL-4受体来减弱IL-13信号传导。但是，决定小鼠IL-13对不同受体的特异性和亲和力的分子决定因素在很大程度上未知。在这里，我们使用高密度重叠的肽阵列，结构建模和分子对接方法来绘制其受体上的IL-13结合序列。小鼠IL-13Rα1和IL-13Rα2上的预测结合序列与报道的人IL-13受体复合物结构和位置定向的突变分析一致。在IL-13受体之间，特别是在IL-13结合界面上发现了新的结构差异。值得注意的是，在IL-13Rα2上观察到IL-13的其他结合位点。另外，IL-13Rα1独有的肽序列的鉴定使我们能够生成一种选择性结合IL-13Rα1的单克隆抗体。因此，与分子对接研究结合使用的高密度肽阵列为映射细胞因子受体相互作用提供了一种新颖，快速且可靠的方法，可用于产生信号传导和诱饵受体特异性拮抗剂，可用于阻断血吸虫病诱导的肝纤维化。 2）尽管有效地治疗了血块性感染的化学疗法，但重新感染率极高。对重新感染的抵抗力可能会发展出来，但是在大量的治疗和重新感染之后，通常需要几年的时间，并且通常仅在一小部分个体中发展。使用公认且高度允许的小鼠模型，我们研究了免疫调节机制是否影响抗药性的发展。在praziquantel（PZQ）治疗曼氏链球菌感染小鼠后，我们观察到具有TH1，TH2和TH17反应的特征是显着且混合的抗蠕虫反应。尽管PBMC，肝脏，脾脏和肠系膜淋巴结的抗Worm反应升高，但这并未赋予次要挑战感染的任何保护。由于观察到产生IL-10的CD4+CD44+CD25+GITR+淋巴细胞的显着增加，因此我们假设IL-10阻碍了耐药性的发展。与单独的PZQ治疗相比，在恢复期间，IL-10与PZQ治疗结合使用的封闭性降低了50％以上，这表明IL-10阻碍了获得的耐药性的发展。明显增强了Th1，Th2和Th17响应，蠕虫特异性IgG1，IgG2b和IgE以及循环嗜酸性粒细胞的特征。这项研究表明，在PZQ治疗期间阻止IL-10信号传导可以促进保护性免疫的发展，并提供了一种高效的策略，以防止与曼氏链球菌的重新感染。