Targeting bioactive lipid pathways to prevent anti-filarial adverse reactions

Abstract

Loiasis, lymphatic filariasis (LF) and onchocerciasis are vector-borne, filarial nematode neglected tropical diseases (NTDs) affecting over 100 million individuals with one billion at risk of infection. With no vaccines or short-course adulticidal curative treatments available, annual mass drug administration programmes (MDA) aim to break transmission when given annually with high adherence covering the reproductive life-span of adult worms (5-12 years). Current MDA drugs include diethylcarbamazine and ivermectin which are direct-acting microfilaricides that rapidly kill microfilarial larvae in the blood or skin. New drugs being re-purposed for human filariasis (emodepside and moxidectin) also similarly rapidly target microfilariae. Microfilaricide MDA is associated with post-treatment inflammatory adverse reactions which in their severest presentation may be life-threatening but more typically causes acute febrile illness, associated with pre-treatment microfilarial burdens and co-infection status. Local knowledge of the risk of debilitating adverse reactions to microfilaricides is a barrier to long-term adherence to MDA treatment in certain communities and hence a vulnerability of current filariasis elimination strategies. We have determined ‘type-2’ eosinophil-dependent inflammation is associated with the post-ivermectin treatment response. We have emergent data indicating both host and parasite-generated bioactive lipid mediators are associated with filarial inflammatory disease pathways. Because inflammatory lipid generation can be blocked with a variety of cheap registered non-steroidal anti-inflammatory drugs, identifying a mechanistic role for bioactive lipid pathways in microfilaricide adverse reactions may promote the use of affordable presumptive adjunct therapies to at-risk communities during MDA cycles. 

In this project, embedded within a multi-disciplinary MRC Programme awarded to the supervisory team (Filariasis Lipids in Pathogenesis; FLiP), you will investigate the role of bioactive lipids in type-2 immune-dependent filarial inflammation during acute microfilaricide adverse reactions

The aims of the project are to:

1. detail the bioactive lipidomes upregulated following experimental or clinical microfilaricide treatments
2. determine the parasite and host cellular sources of bioactive lipids following treatment
3. examine the functions of bioactive lipids in terms of inducing or exacerbating type-2 inflammation
4. identify pharmacological and/or dietary interventions targeting specific bioactive lipid pathways which can ameliorate microfilaricide type-2 inflammation

Where does the project lie on the Translational Pathway?

T1 – Basic Research

T2 Human / Clinical Research

Expected Outputs

We anticipate the characterisation of bioactive lipid changes related to microfilaricidal treatment as minimally sufficient for at least one research publication due to the novelty of the research area and rigour of methods applied. Demonstrating mechanistic links with type-2 inflammation and/or drug-targeting with registered or novel anti-inflammatory agents at a preclinical level should further elevate the significance and impact of the research project for publications in high citation general interest biomedical journals.

Potential for further impact: development of a new adjunct therapy for improved adherence to MDA filariasis elimination programmes

Onward funding: experimental medicine and clinical trials to test relevance and effectiveness of adjunctive therapies.

Training Opportunities

• In vivo filarial infection biology
• Quantitative focussed lipidomics utilising LC-MS/MS
• Cellular and molecular immunology utilising spectral multi-colour flow cytometry, fluorescent-activated cell sorting and focussed protein (Luminex) and transcript (NanoString) arrays.
• immunohistology

Skills Required

We are ideally looking for an enthusiastic talented biomedical science trained student who is interested in developing and applying their skills in translational medicine for global health, with some prior laboratory experience in one or more of the following areas: parasitology, infection biology, molecular biology, (immuno)pharmacology, biochemistry and/or immunobiology.

However, we would welcome applications irrespective of prior experience level.

Key Publications associated with this project

Wanji, S. et al. Advances in Preclinical Platforms of Loa loa for Filarial Neglected Tropical

Disease Drug and Diagnostics Research. Frontiers in Tropical Diseases 2, 778724 (2021)

Forrer, A. et al. Why onchocerciasis transmission persists after 15 annual ivermectin mass drug administrations in South-West Cameroon. BMJ Global Health 6, e003248-29 (2021)

Pionnier, N. et al. Eosinophil-Mediated Immune Control of Adult Filarial Nematode

Infection Can Proceed in the Absence of IL-4 Receptor Signaling. Journal of Immunology (2020)

Pionnier, N. P. et al. Mouse models of Loa loa. Nature Communications 10, 1–11 (2019)