Immunomodulation in chronic Loiasis: a double-edged sword?

点击翻译按钮获取中文摘要

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