The therapeutic potential of targeting bioactive lipids in filariasis

丝虫病是由一群被称为丝虫的线状寄生虫引起的，它们感染血液、眼睛、淋巴管和皮肤。在世界上一些最贫穷的国家中，大约有9000万人感染了丝虫，10亿人处于危险之中。淋巴丝虫病会导致淋巴丝虫病(LF)，它会破坏肢体，这是一种淋巴水肿的形式，俗称为象皮病。患有丝虫淋巴水肿症的人会失去行动能力，并经常经历导致心理问题的社会污名。LF已被归类为全球残疾的主要原因。相关的皮肤寄生丝虫，螺旋体丝虫，在眼睛慢性感染后导致河盲。80万人因盘尾丝虫病而失明或视力受损，其中大多数人生活在撒哈拉以南非洲。通过每年向存在寄生虫的整个社区进行药物治疗，可以防止丝虫向未受感染的个人传播。这些药物可以迅速但暂时地清除体内的微小幼虫(微丝虫)。不幸的是，这些药物不能治愈感染者，也不能阻止LF的淋巴水肿。这意味着，即使消除了自闭症，一代人的残疾也会恶化(估计有3600万人)。目前在非洲可用于消除盘尾丝虫病的药物非常有限。目前只有两种相关药物：伊维菌素和莫西菌素。不幸的是，感染了高水平相关丝虫病病原体Loa Loa的人，在使用伊维菌素治疗时，很容易死于严重的不良反应。由于担心遭受危及生命的反应或生病无法工作，整个社区都不愿参加年度治疗。在许多中非国家，这是消除盘尾丝虫病的障碍，在这些国家，盘虫病是共同流行的。因此，世界卫生组织呼吁采取新的方法来加快消除丝虫病，以减轻受影响个人、他们的家庭和社区的痛苦，改善他们的日常生活。制定了到2030年将发病率降低75%以上的雄心勃勃的目标。我们以前的工作表明，一种独特的炎性免疫反应-2型炎症，也是导致变态反应性疾病和哮喘的原因，在淋巴丝虫病的实验模型中触发淋巴病理。2型炎症也与伊维菌素不良反应有关。在这些数据的基础上，我们现在有了令人兴奋的试点数据，表明在2型炎症过程中释放的特殊脂质代谢物，称为生物活性脂类，可能通过诱导组织中的致病变化直接导致疾病，或者作为启动或放大2型炎症的刺激。在任何一种情况下，这都是治疗丝虫病的潜在的改变游戏规则的解决方案，因为有一系列可用的、廉价的、安全的治疗方法可以降低血液中的水平。这类药物(非类固醇消炎药)每天被数千万人用于治疗痛风或哮喘。因此，在我们的研究计划中，我们将开发一种灵敏而特异的方法来同时测量伊维菌素治疗前或治疗后的血吸虫病患者、患有淋巴水肿的肝病患者或感染血吸虫病或肝病的小鼠的一套全面的生物活性脂质水平。我们将与健康或未感染的样本比较，确定与疾病相关的主要代谢物的特征。然后，我们将在小鼠身上进行研究，以确定特定的生物活性脂质如何与2型炎症相互作用而导致疾病。最后，我们将确定在阻断疾病方面最有效的口服药物疗法，这些疗法可以迅速推广到临床测试中。

Filarial diseases are caused by a group of thread-like parasitic worms, known as filariae, which infect the blood, eyes, lymphatics and skin. Around 90 million people in some of the world's poorest nations are infected with filariae and 1 billion are at risk. Lymphatic dwelling filariae cause lymphatic filariasis (LF) which can disfigure the limbs, a form of lymphoedema known colloquially as elephantiasis. People with filarial lymphoedema suffer from loss of mobility and often experience social stigmatisation leading to psychological problems. LF has been classified as a leading cause of global disability. The related skin dwelling filariae, Onchocerca volvulus, causes river blindness following chronic infection of the eye. Eight hundred thousand people are blind or suffer visual impairment because of onchocerciasis, the majority of whom live in sub-Saharan Africa. Spread of filariae to uninfected individuals can be prevented by annual treatment with drugs to whole communities where the parasites are present. These drugs work to rapidly but temporarily to remove microscopic larvae (microfilariae) from the body. Unfortunately, these drugs do not cure infected individuals nor do they stop lymphoedema in LF. This means that even if LF elimination is achieved, a generation of people will be left with a worsening disability (an estimated 36 million individuals). The current drugs available to eliminate onchocerciasis in Africa are very limited. Only two related drugs; ivermectin and moxidectin are available. Unfortunately, people who are infected with high levels of the related filarial pathogen Loa loa, are vulnerable to succumbing to severe adverse reactions when treated with ivermectin. This dissuades whole communities from taking part in annual treatments due to concerns of suffering life-threatening reactions or being sick and not being able to work. This is a barrier to onchocerciasis elimination in many Central African countries where loiasis is co-endemic. The WHO therefore, has called for new approaches to accelerate elimination of filariasis to alleviate the suffering and improve the daily life of affected individuals, their families and communities. Ambitious targets of reducing morbidity by more than 75% by 2030 have been set. Our previous work has shown that a distinct type of inflammatory immune response, type-2 inflammation, which is also responsible for causing allergic disease & asthma, triggers lymphatic pathology in an experimental model of lymphatic filariasis. Type-2 inflammation also is associated with ivermectin adverse reactions in loiasis. Building on this data, we now have exciting pilot data that suggests specialized lipid metabolites released during type-2 inflammation, called bioactive lipids, might be either directly causing disease by inducing pathogenic changes in tissues or by acting as a stimulus for the initiation or amplification of type-2 inflammation. In either situation, this is a potential game-changing solution to treat filarial disease because a range of available, cheap & safe therapies are available which can lower levels in the blood. Such medications (non-steroidal anti-inflammatory drugs) are used for the treatment of, for instance, gout or asthma by tens of millions of people every day. Therefore, in our research programme we will develop a sensitive and specific method to simultaneously measure levels of a comprehensive set of bioactive lipids in loiasis patients before or after treatment with ivermectin, in LF patients with lymphoedema or in mice infected with either loiasis or LF. We will characterise the major metabolites associated with disease compared with healthy or uninfected samples. We will then undertake studies in mice to determine how specific bioactive lipids interact with type-2 inflammation to cause disease. Finally, we will identify the most effective oral drug therapies effective in blocking disease that can be rapidly promoted into clinical testing.