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.

丝状疾病是由一组螺纹状的寄生虫蠕虫（称为丝状虫）引起的，这些蠕虫被称为丝状蠕虫，它们感染了血液，眼睛，淋巴管和皮肤。世界上一些最贫困国家中约有9000万人感染了丝状，有10亿人处于危险之中。淋巴住宅丝状菌丝引起淋巴丝虫病（LF），这会毁容四肢，这是一种通俗地称为象超症的淋巴水肿的一种形式。丝状淋巴水肿的人遭受流动性丧失，经常遭受社会污名化，导致心理问题。 LF已被归类为全球残疾的主要原因。相关的皮肤住宅，onChocerca volvulus，眼睛长期感染后会引起河流失明。八十万人因脑尾症而蒙蔽或遭受视觉障碍，其中大多数居住在撒哈拉以南非洲。通过用药物治疗对存在寄生虫的整个社区，可以预防丝状丝状发育症。这些药物可以快速但暂时地从体内去除微量幼虫（微丝菌）。不幸的是，这些药物无法治愈感染的个体，也不能阻止LF中的淋巴水肿。这意味着，即使实现了LF消除，一代人也会遭受恶化的残疾（估计有3600万人）。目前可用于消除非洲各种尾cer虫的药物非常有限。只有两种相关药物；伊维菌素和莫昔迪克蛋白可用。不幸的是，当用伊维菌素治疗时，患有高水平的相关病原体LOA的人感染了高水平的丝状病原体LOA LOA。由于担心遭受威胁生命的反应或生病而无法工作，因此整个社区无法参加年度治疗。这是在许多中非地区的中非国家中消除con绕的障碍的障碍。因此，谁呼吁采用新的方法来加速消除丝虫病，以减轻痛苦并改善受影响的个人，家庭和社区的日常生活。到2030年已经设定了将发病率降低75％以上的雄心勃勃的目标。我们以前的工作表明，炎症2型炎症的独特类型，也是导致过敏性疾病和哮喘的原因，在淋巴丝虫病实验模型中触发淋巴病理学。 2型炎症也与叶虫中的伊维菌素不良反应有关。在这些数据的基础上，我们现在拥有令人兴奋的试验数据，该数据表明在2型炎症期间释放的专门脂质代谢产物（称为生物活性脂质）可能是通过诱导组织的致病性变化而直接引起疾病的，或者是通过刺激刺激了2型炎症的启动或扩增。在任何一种情况下，这都是一种可能改变游戏规则的解决方案，可以治疗丝状疾病，因为有一系列可用的廉价且安全的疗法可以降低血液中的水平。这种药物（非甾体类抗炎药）每天都使用数千万人来治疗，例如痛风或哮喘。因此，在我们的研究计划中，我们将开发一种敏感和具体的方法，以同时测量在用伊维菌素治疗前或治疗后，在淋巴水肿或感染了Loiasis或LF的小鼠的LF患者中，在Loiasis患者中的一组综合生物活性脂质水平。与健康或未感染的样品相比，我们将表征与疾病相关的主要代谢产物。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，我们将确定有效阻止疾病的最有效的口服药物疗法，可以迅速促进临床测试。