The therapeutic potential of targeting bioactive lipids in filariasis
Lead Research Organisation:
Liverpool School of Tropical Medicine
Department Name: Tropical Disease Biology
Abstract
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.
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.
Technical Summary
Loiasis, lymphatic filariasis (LF) & onchocerciasis (river blindness) are filarial nematode diseases. LF causes the major global disability, lymphoedema (LE). Onchocerciasis (river blindness) is a leading cause of visual impairment. These neglected tropical diseases (NTDs) are prioritised for global or regional elimination. Annual drug treatment for 6-15 years using anthelmintics such as ivermectin (IVM), target microfilariae to break transmission but do not improve pre-existing morbidity. No scalable pharmacological treatment is available for filarial LE. Loiasis causes adverse reactions (AR) following IVM treatment and presents a barrier to elimination of onchocerciasis. The WHO NTD 2030 Roadmap calls for innovations in therapies for LF & onchocerciasis as a critical requirement to reduce morbidity attributed to these NTDs.
We have previously shown that type-2 immune-mediated inflammation is associated with loiasis IVM AR and is causal in LF lymphatic pathology. Now we have extensive pilot data indicating bioactive lipid metabolites produced in both scenarios are implicated in pathology. This is exciting because a range of registered, affordable & safe therapies are available which can target biolipid enzymes or receptors. These could be deployed at scale in resource poor settings to treat LF morbidity and protect IVM-based elimination strategies. In this multidisciplinary programme we will develop a multiplex LC/MS-MS bioanalytical platform to quantify a range of lipid metabolites representing the bioactive lipidome. We will utilise our innovations in loiasis and LF infection models and clinical samples to characterise the major metabolites associated with disease. We will undertake genetic and immunological loss of function studies to investigate mechanisms of bioactive lipids in type-2 inflammation and disease formation. Finally, we will identify pharmacological therapies effective in blocking experimental pathology that can be promoted into clinical testing.
We have previously shown that type-2 immune-mediated inflammation is associated with loiasis IVM AR and is causal in LF lymphatic pathology. Now we have extensive pilot data indicating bioactive lipid metabolites produced in both scenarios are implicated in pathology. This is exciting because a range of registered, affordable & safe therapies are available which can target biolipid enzymes or receptors. These could be deployed at scale in resource poor settings to treat LF morbidity and protect IVM-based elimination strategies. In this multidisciplinary programme we will develop a multiplex LC/MS-MS bioanalytical platform to quantify a range of lipid metabolites representing the bioactive lipidome. We will utilise our innovations in loiasis and LF infection models and clinical samples to characterise the major metabolites associated with disease. We will undertake genetic and immunological loss of function studies to investigate mechanisms of bioactive lipids in type-2 inflammation and disease formation. Finally, we will identify pharmacological therapies effective in blocking experimental pathology that can be promoted into clinical testing.
