权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Crosstalk of macrophages and eosinophils in helminth-mediated protection during experimental sepsis

实验性脓毒症期间巨噬细胞和嗜酸性粒细胞在蠕虫介导的保护中的串扰

基本信息

批准号：
232391168
负责人：
Professor Dr. Marc Hübner
金额：
--
依托单位：
Institut für Medizinische Mikrobiologie, Immunologie und Parasitologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2013
资助国家：
德国
起止时间：
2012-12-31 至 2016-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/232391168?language=en
关键词：
Crosstalk macrophages eosinophils helminth mediated

项目摘要

Sepsis occurs when bacteria enter the blood stream. Accompanying, excessive immune activation during sepsis causes pathology and eventual death by multi-organ failure. The ultimate goal of this project is to identify mechanisms to suppress this excess inflammation without impeding clearance of the bacterial infection. We postulate that investigating the effects helminth infections have on the immune response that develops during sepsis will enable us to identify such mechanisms. In contrast to bacteria, filarial helminth species release up to millions of microfilariae (progeny of filaria) per milliliter of blood without inducing inflammation. To avoid inflammation, helminths modulate the hosts immune system and induce an anti-inflammatory, suppressive milieu. Experimental studies showed that immunomodulation by helminths prevent or improve allergies and autoimmune diseases. However, the impact of chronic helminth infections on acute systemic pro-inflammatory immune responses like sepsis is scarcely understood. Using the only mouse model of filariasis that allows chronic filarial infection, we were able to show that chronic infection of mice with the filarial nematode Litomosoides sigmodontis (Ls) improves clearance of i.p. injected E. coli bacteria and ameliorates hypothermia. Chronic infection with Ls results in eosinophilia, induction of anti-inflammatory, alternatively activated macrophages (AAM) and reduces E. coli mediated pro-inflammatory immune responses. Depletion of macrophages, eosinophils and anti-inflammatory TGF beta reduces the Ls mediated protective effect against an E. coli challenge.This grant proposal will focus on the role of Ls-modulated macrophages from liver, spleen, and peritoneum as well as eosinophils during an E. coli challenge. Analyzes will include phenotypic and functional characterization as well as gene expression. Transfer and depletion experiments will investigate the role of AAM and TGF beta and unravel which macrophage and eosinophil derived mediators are crucial for the protection against E. coli. The crosstalk of macrophages and eosinophils with neutrophils and mast cells will be analyzed in this context.Following sepsis, a compensatory anti-inflammatory response syndrome (CARS) develops and results in T-cell paralysis that increases the risk for superinfections. As Ls infection efficiently modulates the acute immune response to E. coli, experiments are proposed to test the impact of chronic Ls infection on the adaptive immune response and specific in vivo CD8 T-cell lysis after an E. coli challenge. Further experiments will investigate whether administration of known immunomodulatory filarial antigens protect against E. coli sepsis and CARS. Results of these studies may lead to insights for the development of novel treatments which suppress the excessive inflammation that occurs in sepsis without compromising the bodys ability to clear bacterial infections.

当细菌进入血流时就会发生败血症。随之而来的是，败血症期间过度的免疫激活会导致病理并最终因多器官衰竭而死亡。该项目的最终目标是确定抑制这种过度炎症而不妨碍细菌感染清除的机制。我们假设，研究蠕虫感染对脓毒症期间发生的免疫反应的影响将使我们能够确定此类机制。与细菌相反，丝虫类蠕虫每毫升血液释放多达数百万个微丝蚴（丝虫的后代），而不会引起炎症。为了避免炎症，蠕虫会调节宿主的免疫系统并诱导抗炎、抑制的环境。实验研究表明，蠕虫的免疫调节可以预防或改善过敏和自身免疫性疾病。然而，慢性蠕虫感染对脓毒症等急性全身促炎性免疫反应的影响尚不清楚。使用唯一允许慢性丝虫感染的丝虫病小鼠模型，我们能够证明，丝虫线虫 Litomosoides sigmodontis (Ls) 的小鼠慢性感染可提高腹腔内丝虫的清除率。注射大肠杆菌并改善体温过低。 Ls 的慢性感染会导致嗜酸性粒细胞增多、诱导抗炎、交替激活巨噬细胞 (AAM) 并减少大肠杆菌介导的促炎免疫反应。巨噬细胞、嗜酸性粒细胞和抗炎性 TGF β 的消耗会降低 Ls 介导的针对大肠杆菌攻击的保护作用。该拨款提案将重点研究来自肝脏、脾脏和腹膜的 Ls 调节的巨噬细胞以及嗜酸性粒细胞在大肠杆菌攻击期间的作用。分析将包括表型和功能表征以及基因表达。转移和耗竭实验将研究 AAM 和 TGF beta 的作用，并揭示哪些巨噬细胞和嗜酸性粒细胞衍生的介质对于预防大肠杆菌至关重要。在此背景下，将分析巨噬细胞和嗜酸性粒细胞与中性粒细胞和肥大细胞的串扰。败血症后，会出现代偿性抗炎反应综合征 (CARS)，并导致 T 细胞麻痹，从而增加重复感染的风险。由于 Ls 感染有效调节对大肠杆菌的急性免疫反应，因此建议进行实验来测试慢性 Ls 感染对大肠杆菌攻击后的适应性免疫反应和特异性体内 CD8 T 细胞裂解的影响。进一步的实验将研究施用已知的免疫调节丝虫抗原是否可以预防大肠杆菌败血症和 CARS。这些研究的结果可能有助于开发新的治疗方法，抑制脓毒症中发生的过度炎症，而不损害身体清除细菌感染的能力。