Eosinophil and neutrophil ETosis during human filarial infection

人类丝虫感染期间的嗜酸性粒细胞和中性粒细胞 ETosis

• 批准号: 461670784
• 负责人: Professor Dr. Marc Hübner
• 金额: --
• 依托单位: Department of Microbiology and Parasitology
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/461670784?language=en
• 关键词: Eosinophil; neutrophil; ETosis; during; human

Filariae can cause debilitating diseases in humans such as onchocerciasis, which can lead to severe dermatitis and blindness. However, not all onchocerciasis patients develop these clinical pictures and other filarial species often cause mild infections. Granulocytes are involved in the development of onchocerciasis-induced symptoms by triggering inflammatory responses to dying microfilariae (MF), the progeny of filariae. Our own studies with the rodent filariae Litomosoides sigmodontis show that eosinophil and neutrophil granulocytes are essential for protective immune responses in the mouse model. Here, we discovered that MF induce the release of extracellular DNA nets (ETosis) from eosinophils via Dectin-1, thereby supporting MF elimination. Interestingly, dead MF trigger a stronger ETosis response via a different signaling cascade. Based on these observations in the mouse model, we hypothesize that human MF also induce ETosis and that this is enhanced in granulocytes from onchocerciasis patients with clinical symptoms. Therefore, in the present application we would like to compare eosinophils and neutrophils from onchocerciasis patients with and without clinical manifestations as well as endemic, non-infected individuals. In particular, their ability to induce MF-induced ETosis will be investigated. In addition, we will analyze whether MF of different filarial species differ in their ability to induce ETosis. We hypothesize that filarial species that generally lead to mild infections (Mansonella, Loa) induce weaker ETosis responses than filarial species that cause clinical manifestations (Onchocerca). Furthermore, we hypothesize that dead MF induce a stronger ETosis than live MF due to the recognition of endosymbiotic Wolbachia bacteria, which induce a different signaling cascade. Analysis of granulocyte ETosis with Wolbachia-containing filariae (Onchocerca, Mansonella) and Wolbachia-free filariae (Loa) as well as live and dead MF with blocking antibodies for different pattern recognition receptors will clarify this. These experiments will be carried out with our long-term collaboration partner Prof. Wanji in Cameroon. For this purpose, a transfer of the state-of-the-art methods for the investigation of ETosis established in Bonn to Cameroon will take place. Within the framework of this project, a female postdoctoral student, two female PhD students and a master student in Cameroon and a postdoctoral student in Bonn will be supported and workshops will be given to train additional students. Prof. Wanji has access to filariasis patients and the proven expertise and infrastructure to cultivate human filariae in vitro and perform immunological studies. Thus, the aim of this application is to transfer the latest findings in filarial-induced ETosis from animal models to humans, for which Prof. Wanji's laboratory is perfectly suited.

丝虫病可引起人类衰弱性疾病，如盘尾丝虫病，可导致严重的皮炎和失明。然而，并非所有盘尾丝虫病患者都会出现这些临床症状，其他丝虫病种通常会引起轻度感染。粒细胞通过引发对死亡微丝虫病（丝虫病的后代）的炎症反应，参与盘尾丝虫病诱导症状的发展。我们对啮齿动物丝虫病的研究表明，在小鼠模型中，嗜酸性粒细胞和中性粒细胞对保护性免疫反应至关重要。在这里，我们发现MF通过Dectin-1诱导嗜酸性粒细胞释放细胞外DNA网（ETosis），从而支持MF消除。有趣的是，死亡的MF通过不同的信号级联触发更强的ETosis反应。基于这些在小鼠模型中的观察结果，我们假设人类MF也会诱导ettosis，并且这种情况在有临床症状的盘尾丝虫病患者的粒细胞中得到增强。因此，在目前的应用中，我们想比较嗜酸性粒细胞和中性粒细胞来自盘尾丝虫病患者和无临床表现，以及地方病，非感染者。特别是，它们诱导mf诱导的ettosis的能力将被研究。此外，我们将分析不同菌种的MF诱导ETosis的能力是否存在差异。我们假设通常导致轻度感染的丝虫病种（Mansonella, Loa）比引起临床表现的丝虫病种（盘尾丝虫病）诱导较弱的ETosis反应。此外，我们假设死亡的MF比活的MF诱导更强的ettosis，这是由于对内共生沃尔巴克氏菌的识别，它们诱导不同的信号级联。分析含沃尔巴克氏体丝虫（盘尾丝虫、曼索菌）和无沃尔巴克氏体丝虫（Loa）的粒细胞凋亡，以及具有不同模式识别受体阻断抗体的活MF和死MF，将澄清这一点。这些实验将与我们在喀麦隆的长期合作伙伴Wanji教授一起进行。为此目的，将把在波恩建立的最先进的ETosis调查方法转移到喀麦隆。在该项目的框架内，将支持喀麦隆的一名女博士后、两名女博士和一名硕士生，以及波恩的一名博士后，并将举办讲习班培训更多的学生。万吉教授可以接触到丝虫病患者，并拥有成熟的专业知识和基础设施，可以在体外培养人类丝虫病并进行免疫学研究。因此，本申请的目的是将丝虫病诱导的体外代谢的最新发现从动物模型转移到人类身上，Wanji教授的实验室非常适合。