Immunomodulation in chronic Loiasis: a double-edged sword?

由丝虫病Loa Loa引起的丝虫病是影响人类的第三种丝虫病。该病影响中非和西非部分地区约1000万人，是一种被忽视的热带病，迄今为止得到的研究关注不足。眼珠病通常被认为是一种良性感染，仅伴有“眼虫”和其他非致命性症状，如卡拉巴肿胀、瘙痒和关节痛，尽管这些症状仍会引起显著的累积发病率。此外，虱子病还可能在其他热带传染病的情况下造成有害影响，可能是通过其对人体免疫系统的影响：虱子菌感染可能与两种截然相反的免疫调节形式有关。一方面，慢性感染可持续多年，成虫可通过皮下组织迁移，甚至血液中微丝蚴含量很高，但不会引起强烈症状或发烧。这表明这些寄生虫对免疫系统有很强的抑制作用。目前尚不清楚这种免疫抑制是否也会降低对疟疾等其他感染的免疫力。另一方面，血液中含有大量罗氏微丝虫病的患者在接受微丝虫病杀丝药物（如DEC或伊维菌素）治疗时，可迅速出现危及生命的炎症副作用，如脑病。这一危险阻碍了大规模药物管理（MDA）运动在Loa共同流行地区消灭淋巴丝虫病和河盲症。我们项目的目的是通过测量加蓬和贝宁路易丝虫流行人群以及接受抗丝虫药物治疗的患者的免疫反应，研究路易丝虫“双刃剑”的两面。在加蓬，我们将分析在横断面流行病学研究和纵向减少传播研究中收集的血液样本。在贝宁，我们将组织一项小型的有针对性的实地研究，从感染艾滋病的受试者身上收集免疫学样本。使用这些样本，我们将测量促炎和抗炎反应之间的一般平衡，并更详细地关注三个关键的白细胞群：嗜酸性粒细胞、调节性T细胞和髓源性抑制细胞。我们还将评估对免疫反应的影响，例如疟疾寄生虫。最后，我们将建立一个体外刺激模型来描述参与对活微丝虫和死微丝虫反应的免疫机制。这一认识最终将导致干预措施，不仅有利于丝虫病患者（更安全的治疗和减轻症状），而且有利于更广泛的医疗领域（更广泛地推出消除丝虫病的MDA运动和治疗自身免疫性疾病等潜在的新战略）。在这个过程中，我们将培养一系列年轻的非洲科学家，使他们成为自己的免疫学研究人员

Loiasis, caused by the filarial nematode Loa loa, is the third type of filariasis affecting humans. It affects an estimated >10 million people in Central and parts of Western Africa and truly represents a neglected tropical disease, receiving undeservedly sparse research attention until now. Loiasis is often considered a benign infection, associated only with “eye-worm” and other non-lethal symptoms like Calabar swellings, pruritus and arthralgia, although these still cause significant cumulative morbidity. Furthermore, loiasis can also cause detrimental effects in the context of other tropical infectious diseases, presumably through its effects on the human immune system:Infection with L. loa can be associated with two, diametrically opposed, forms of immunomodulation. On the one hand chronic infections can persist for many years, with adult worms migrating through subcutaneous tissue and even with high levels of microfilaria in the blood, without causing strong symptoms or fever. This suggests that these parasites exert a strong suppressive effect on the immune system. It is currently unknown whether this immunosuppression also reduces immunity against other infections, such as malaria. On the other hand, patients with high numbers of Loa microfilariae in their blood who are treated with microfilaricidal drugs (e.g. DEC or ivermectin), can quickly develop life-threatening inflammatory side-effects such as encephalopathy. This danger has prevented Mass Drug Administration (MDA) campaigns for the elimination of lymphatic filariasis and river-blindness taking place in Loa co-endemic areas.The aim of our project is to study both sides of Loa’s ‘double-edged sword’, by measuring immune responses in loiasis-endemic populations in Gabon and Benin, as well as in patients undergoing treatment with anti-filarial drugs. In Gabon we will analyse blood samples collected in the context of a cross-sectional epidemiological study and a longitudinal transmission-reduction study. In Benin we will organise a small targeted field study to collect immunological samples from Loa-infected subjects. Using these samples we will measure the general balance between pro- and anti-inflammatory responses and focus in more detail on three key leukocyte populations: eosinophils, regulatory T cells and myeloid-derived suppressor cells. We will also assess effects on immune responses against e.g. malaria parasites. Finally, we will develop an in vitro stimulation model to delineate the immunological mechanisms involved in the response to live and dead microfilariae.This insight should ultimately lead to interventions that benefit not only loiasis patients (safer treatment and symptom reduction), but also the wider medical field (wider roll-out of MDA campaigns for filariasis-elimination and potential new strategies for treating e.g. auto-immune diseases). In the process, we will train a series of young African scientists to become immunological researchers in their own right