Eosinophil and neutrophil ETosis during human filarial infection

点击翻译按钮获取中文摘要

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.