Immunomodulation in chronic Loiasis: a double-edged sword?

慢性罗阿病的免疫调节：一把双刃剑？

• 批准号: 380627074
• 负责人: Dr. Matthew McCall
• 金额: --
• 依托单位: Afdeling Medische Microbiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/380627074?language=en
• 关键词: Immunomodulation; chronic; Loiasis; double; edged

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

由Loa loa丝虫引起的Loalis是影响人类的第三种丝虫病。在中非和西非部分地区，估计有1 000多万人受到影响，这确实是一种被忽视的热带疾病，迄今为止，人们对它的研究很少。Loplasty通常被认为是一种良性感染，仅与“眼虫”和其他非致命症状如Calabar皮肤炎，瘙痒和关节痛有关，尽管这些仍然会导致显著的累积发病率。此外，在其他热带传染病的背景下，洛氏杆菌也可能引起有害影响，可能是通过其对人类免疫系统的影响：LOA可以与两种完全相反的免疫调节形式相关。一方面，慢性感染可以持续多年，蠕虫通过皮下组织迁移，甚至血液中有高水平的微丝蚴，而不会引起强烈的症状或发烧。这表明这些寄生虫对免疫系统产生强烈的抑制作用。目前尚不清楚这种免疫抑制是否也会降低对其他感染（如疟疾）的免疫力。另一方面，血液中有大量Loa微丝蚴的患者接受杀微丝蚴药物（如DEC或伊维菌素）治疗后，可能会迅速出现危及生命的炎症副作用，如脑病。这种危险阻止了大规模药物管理局（MDA）在Loa共同流行地区开展消除淋巴丝虫病和河盲症的运动。我们项目的目的是研究Loa“双刃剑”的两面，通过测量加蓬和贝宁的Loiasis流行人群以及正在接受抗丝虫药物治疗的患者的免疫反应。在加蓬，我们将分析在跨部门流行病学研究和减少传播纵向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Loa的受试者中收集免疫学样本。使用这些样本，我们将测量促炎反应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体：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，我们将开发一个体外刺激模型，以描述参与对活的和死的微丝蚴的反应的免疫机制。这一见解最终将导致干预措施，不仅有利于丝虫病患者（更安全的治疗和症状减轻），而且有利于更广泛的医疗领域（更广泛地推出MDA运动消除丝虫病和治疗自身免疫性疾病的潜在新策略）。在此过程中，我们将培养一批非洲年轻科学家，使他们成为独立的免疫学研究人员