Is targeting vascular remodelling by filarial parasites a viable anti-morbidity solution?

丝虫病是由一组被称为丝虫病的线状寄生虫引起的。丝虫病影响社会的“底层十亿人”；世界上一些最贫穷的国家有1.5亿人受到感染，13亿人面临感染的风险。淋巴寄生丝虫病引起淋巴丝虫病（LF），其最严重的形式表现为四肢或生殖器毁容，称为象皮病。象皮病患者丧失行动能力，影响日常活动，并经常遭受社会歧视和心理问题。世界卫生组织将LF列为全球致残的第二大原因。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。估计有80万人因盘尾丝虫病而视力受损，主要是在撒哈拉以南非洲。每年对流行社区进行治疗可阻断丝虫病的传播。不幸的是，这些药物不能治愈受感染的个体，也不能阻止象皮病的发展。这意味着，如果消灭LF得以实现，将会有一代人（约4000万人）的残疾状况逐渐恶化。目前的药物也非常有限（只有一种药物可用于盘尾丝虫病），并且在长期使用后容易产生耐药性。目前的盘尾丝虫病治疗似乎不能帮助逆转河盲症的早期视力损害。因此，需要采取新的方法来解决丝虫病发病率问题，以减轻丝虫病患者、其家庭和社区的痛苦并改善其日常生活。为了实现这一目标，需要充分了解丝虫病是如何引起疾病的，以及一部分受感染个体是如何避免发展成病理的。对丝虫病过程的深入了解将有助于确定现有药物或新改进的实验性治疗方法可能针对的疾病途径。本研究将探讨血液和淋巴重塑在丝虫病发病机制中的作用。在丝虫病患者中，血液循环中血管生成（血管生长）的标志物增加。在盘尾丝虫病中，视力丧失与血管渗漏有关，在河盲症小鼠模型中，在丝虫病炎症期间发生血液扩张和新血管生长。然而，尚不清楚血液重塑事件是如何被诱导的，它们在推动疾病发展中有多重要，或者它们是否提供了合适的“可药物”抗发病率目标。我们的实验室最近发现，丝虫的直接炎症导致一组重要的促血管生成分子，血管内皮生长因子（vegf）的上调，刺激血管重塑并导致血管泄漏。通过提供一种改良的VEGF生长因子信号，它只能激活淋巴而不能激活血管，我们有证据表明，这改善了丝虫炎症的病理后果。在本提案中，我将利用小鼠LF和河盲症的临床前病理模型研究vegf特异性血液激活在丝虫病过程中的重要性。我将评估在LF感染期间自然诱导的淋巴修复的假定宿主免疫机制以及与此过程相关的前淋巴管生成反应。然后，我将测试靶向血液重塑的治疗价值，包括VEGF途径和淋巴再生过程，以改善LF或河盲症病理。我将测试可以在不久的将来转化为治疗方法的注册药物，以及下一代“生物”干预措施，随着生物制剂继续被纳入主流医学，这些干预措施可能变得更便宜。

Filariasis is caused by a group of thread-like parasitic worms, known as filariae. Filariasis affects the 'bottom billion' of society; 150 million people in some of the world's poorest nations are infected and 1.3 billion are at risk of infection. Lymphatic dwelling filariae cause lymphatic filariasis (LF), which, in its most severe form, manifests as disfigurement of the limbs or genitals, known as elephantiasis. People with elephantiasis suffer from loss of mobility affecting daily activities and often experience social stigmatisation and psychological problems. The WHO classifies LF as the second leading cause of global disability. The related skin dwelling filariae, Onchocerca volvulus, causes the disease river blindness following chronic infection of the eye. An estimated 800,000 people suffer visual impairment as a result of onchocerciasis, mainly in sub-saharan Africa. Transmission of filariasis can be blocked by annual treatments to endemic communities. Unfortunately, these drugs do not cure infected individuals nor do they stop the progression of elephantiasis. This means that if LF elimination is achieved, a generation of people will be left with a gradually worsening disability (~40 million individuals). Current drugs are very also limited (only a single drug is available for onchocerciasis) and are vulnerable to the development of resistance after their protracted use. The current onchocerciasis treatment does not appear to help reverse the early visual impairment of river blindness. Therefore, new approaches to tackling filarial morbidity are required to alleviate the suffering and improve the daily life of filariasis disease sufferers, their families and communities. Toward this aim, a full understanding of how filarial parasites cause disease and how a proportion of infected individuals avoid developing pathology is required. A deeper understanding of filarial disease processes will facilitate the identification of disease pathways that can be potentially targeted by either current drugs or new improved experimental treatments. This proposal will examine the role of blood and lymphatic remodeling in the pathogenesis of filariasis. In filarial pathology patients, markers of angiogenesis (growth of blood vessels) are increased in the circulation. In onchocerciasis, loss of visual acuity is associated with leaky blood vessels and in a mouse model of river blindness, blood dilation and growth of new vessels occurs during filarial inflammation. However, it is not known how blood remodeling events are induced, how important they are in driving development of disease or whether they offer suitable 'druggable' anti-morbidity targets. Our laboratory has recently identified that direct inflammation by filarial worms causes both the upregulation of a group of important pro-angiogenic molecules, the vascular endothelial growth factors (VEGFs), stimulates remodeling of blood vessels and causes vascular leak. By providing a modified VEGF growth factor signal that can only activate lymphatic but not blood vessels, we have evidence that this improves the pathological ramifications of filarial inflammation. In this proposal I will investigate the importance of VEGF-specific blood activation in filarial disease processes using murine pre-clinical pathology models of LF and river blindness. I will assess a putative host immunological mechanism of lymphatic repair that is induced naturally during LF infection and the pro-lymphangiogenic responses that this process is associated with. I will then test the therapeutic value of targeting blood remodeling, including the VEGF pathway and lymphatic regenerative processes in ameliorating LF or river blindness pathologies. I will test both registered drugs that could be translated into therapies in the immediate future as well as next generation 'biologic' interventions that could become more cost-affordable as biologics continue to be incorporated into mainstream medicine.