The therapeutic potential of targeting bioactive lipids in filariasis

丝虫病靶向生物活性脂质的治疗潜力

• 批准号: MR/X001911/1
• 负责人: Joseph Turner
• 金额: $ 211.98万
• 依托单位: Liverpool School of Tropical Medicine
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX001911%2F1
• 关键词: therapeutic; potential; targeting; bioactive; lipids

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.

丝虫病是由一组线状寄生蠕虫引起的，称为丝虫，它感染血液，眼睛，皮肤和皮肤。在世界上一些最贫穷的国家，约有9 000万人感染丝虫病，10亿人处于危险之中。淋巴丝虫引起淋巴丝虫病（LF），可导致四肢毁容，这是一种淋巴水肿，通俗地称为象皮病。患有丝虫性淋巴水肿的人会丧失行动能力，并经常遭受社会污名化，导致心理问题。LF已被列为全球残疾的主要原因。相关的皮肤寄生丝虫，盘尾丝虫，在眼睛慢性感染后引起河盲症。80万人因盘尾丝虫病失明或视力受损，其中大多数生活在撒哈拉以南非洲。丝虫向未感染个体的传播可以通过每年对存在寄生虫的整个社区进行药物治疗来预防。这些药物的工作迅速，但暂时消除微观幼虫（微丝蚴）从体内。不幸的是，这些药物不能治愈感染的个体，也不能阻止LF的淋巴水肿。这意味着，即使实现了LF消除，一代人的残疾状况仍将恶化（估计有3600万人）。目前可用于消除非洲盘尾丝虫病的药物非常有限。只有两种相关药物：伊维菌素和莫昔克丁可用。不幸的是，感染了高水平相关丝虫病原体Loa loa的人在使用伊维菌素治疗时容易出现严重的不良反应。由于担心出现危及生命的反应或生病而无法工作，整个社区都不愿参加年度治疗。这是消除盘尾丝虫病的一个障碍，在许多中部非洲国家，盘尾丝虫病是共同流行的。因此，世卫组织呼吁采取新的方法加快消除丝虫病，以减轻痛苦，改善受影响个人、家庭和社区的日常生活。已经制定了到2030年将发病率降低75%以上的宏伟目标。我们以前的工作已经表明，一种不同类型的炎症免疫反应，2型炎症，这也是导致过敏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学。2型炎症也与伊维菌素的不良反应有关。基于这些数据，我们现在有了令人兴奋的试验数据，表明在2型炎症过程中释放的专门的脂质代谢物，称为生物活性脂质，可能通过诱导组织中的致病性变化或作为2型炎症启动或放大的刺激物而直接引起疾病。在任何一种情况下，这都是治疗丝虫病的一个潜在的改变游戏规则的解决方案，因为有一系列可用的，廉价和安全的疗法可以降低血液中的水平。这些药物（非甾体抗炎药）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和特异性的方法，同时测量伊维菌素治疗前或治疗后，LF患者淋巴水肿或感染lofenib或LF的小鼠中一组全面的生物活性脂质的水平。我们将与健康或未感染的样本相比，检测与疾病相关的主要代谢物。然后，我们将在小鼠中进行研究，以确定特定的生物活性脂质如何与2型炎症相互作用以引起疾病。最后，我们将确定最有效的口服药物治疗，有效地阻止疾病，可以迅速推广到临床试验。