Maternal helminth infection: Immunological and developmental consequences for the offspring

蠕虫（如血吸虫）的一个非凡特性是，它们能够不断调节宿主的免疫系统，以保证自己的生存。针对蠕虫的免疫反应具有潜在的宿主破坏性，因此需要通过各种机制严格控制。有趣的是，这种控制并不局限于蠕虫本身，而是扩展到不相关的抗原，如过敏原，我们之前在过敏性气道炎症模型中表明，血吸虫感染的小鼠部分通过扩大Treg细胞免受疾病的保护。我们最近开始研究的一个全新的卫生假说研究领域的问题是，这种慢性非经胎盘感染的深刻免疫影响是否会扩展到下一代。在感染过程中，受感染的雌性在三个连续和不同的免疫阶段交配所产生的后代要么部分或几乎完全免受过敏性气道炎症的影响，要么表现出疾病的加重。在这些不同的感染阶段，子代的过敏敏感性反映在不同的胎盘基因表达、细胞因子环境和子代早期免疫细胞组成上。此外，我们发现，在感染的急性期，母体来源的干扰素γ是后代保护性免疫表型的重要因素。可以排除这些血吸虫诱导的效应通过种系遗传的可能性。综上所述，我们假设母亲体内血吸虫诱导的免疫反应改变了胎盘环境，从而从表观遗传上影响了造血系统的发育，从而塑造了后代对过敏和感染的易感性。本提案的主要目的是详细研究三个免疫阶段对后代免疫系统发育的影响，从配子期和胚胎期的改变开始，研究老年后代和F2代的过敏性气道炎症表型。因此，我们的目标是帮助我们理解我们的免疫系统是如何在进化蠕虫压力下进化的，以及这如何有助于第三世界国家低过敏率的流行病学发现。

An extraordinary attribute of helminths, such as schistosomes, is their capability to constantly modulate their hosts immune system in order to guarantee their own survival. Immune responses against the helminth are potentially host-destructive and therefore need to be tightly controlled by a variety of mechanisms. Interestingly, this control is not limited to the helminth itself but expands to unrelated antigens such as allergens and we have shown previously in a model of allergic airway inflammation that schistosome infected mice are protected from disease partially by expanding Treg cells. A completely new question in this field of Hygiene- Hypothesis-related research that we started to address recently is, whether the profound immunological effects of this chronic, non-transplacental infection expand to the next generation. Offsprings generated by mating of infected females during the three consecutive and distinct immune phases elicited during the course infection were either partially or almost completely protected from allergic airway inflammation or showed aggravation of the disease. During these different phases of infection the offsprings allergy susceptibility was reflected in distinct placental gene expression, cytokine environment and the offsprings early immune cell composition. Moreover, we identified that maternal-derived Interferon-gamma during the acute phase of infection is an essential element for the progenys protective immune phenotype. Inheritance of these schistosome-induced effects through the germline could be excluded. Taken together, we hypothesize that schistosome-induced immune responses in the mother change the placental environment which epigenetically affects the development of the hematopoietic system and thereby shapes the offsprings susceptibility to allergies and infections. The main objectives within this proposal are to investigate in detail the impact of the three immune phases on the development of the offsprings immune system, starting from alterations at the gametic and embryonic stage to investigation of the allergic airway inflammation phenotype in aged offspring and the F2 generation. We thereby aim to aid our understanding of how our immune system evolved under evolutionary helminthic pressure and how this contributes to the epidemiological findings of low allergy rates in third world countries.