Bioactive lipid mediators: anti-morbidity drug targets in filariasis?

Lymphatic filariasis (LF) is a filarial nematode infection of medical importance. Due to the disabling and stigmatising morbidities invoked by LF (elephantiasis and hydrocele) this neglected tropical diseases is prioritised for elimination via annual mass drug administration (MDA) of ivermectin-based therapies. MDA therapy does not halt the progression of pre-established LF clinical disease.

In the face of potential elimination of LF by 2030, an estimated 40 million LF patients will endure a lifetime of progressive disability.

By modelling lymphatic filariasis pathology in mice caused by the human filaria, Brugia malayi, we have determined a mechanistic role for ‘type-2’ allergic inflammation in mediating lymphatic pathology. Within this model, we have demonstrated elevations in circulating eicosanoid lipid mediators, prostaglandin (PG)E2 and leukotriene (LT)B4, and pilot data suggests anti-inflammatory interventions disrupting these pathways can moderate filarial lymphatic disease.

This project will develop a bioanalytical liquid chromatography-mass spectrometry (LC-MS/MS) lipidomics platform to comprehensively survey eicosanoid and dietary-derived bioactive lipid metabolites (resolvins) significantly up- or down-regulated in the plasma of mice and humans with lymphatic disease.

The project will exploit novel mouse models of filariasis established at LSTM and clinical collaborations in Malawi and Myanmar. The student will benefit from supervision and training within the Centre for Metabolomics Research (CMR), University of Liverpool (http://www.liverpool.ac.uk/integrative-biology/facilities-and-services/metabolomics-research) to undertake method validation, sample analysis and statistical analyses of the data.

Specific objectives will be:

  1. develop and validate an LC-MS/MS multiplex targeted bioactive lipidomics platform
  2. identification of significant up- or down-regulated bioactive lipids in LF infected mouse and human plasma
  3. test whether targeted treatment of eicosanoid enzymatic pathways with non-steroidal anti-inflammatory drugs (NSAIDs) modifies circulating bioactive lipids and reduces filarial disease in mice.

Where does the project lie on the Translational Pathway?

T1 (Basic Research) – T2 (Human/Clinical Research)

Expected Outputs

Project aims will be to:

  1. Determine bioactive lipid biomarkers of LF disease
  2. Assess impact of drug targeting bioactive lipid metabolic pathways in ameliorating LF disease

Completion of aims will comprise a highly novel and impactful original research article in a leading biomedical journal.

Determining a druggable anti-morbidity pathway in LF will be of importance to the field and should spurn clinical trials to assess efficacy in the treatment of filarial lymphoedemas.

The establishment of the bioactive, targeted lipidomics platform will have potential for wide ranging applications in healthcare and biomedicine and may attract future industrial end user adoption.

The data will be used for competitive grant applications to translate findings as a ‘real world’ anti-morbidity adjunct therapy for filarial disease, using affordable, registered anti-inflammatory drugs.

 

Training Opportunities

The student will benefit from an active collaboration with CMR, University of Liverpool, with world leading experts in lipid bioanalysis, to develop and validate a bioactive lipid targeted bioanalysis platform.

The student will be benefit from training in whole animal physiology techniques (including acquiring regulatory licence and animal handling / animal procedures training) at LSTM and University of Liverpool Biological Services unit.

 

Skills Required

As the project is multidisciplinary in nature, this would suit a talented biologist with interests and experience in infection biology or biochemistry.

 

Key Publications associated with this project

Rockson, S. G., Tian, W., Jiang, X., Kuznetsova, T., Haddad, F., Zampell, J., et al. (2018). Pilot studies demonstrate the potential benefits of antiinflammatory therapy in human lymphedema. JCI Insight, 3(20), 78–11. http://doi.org/10.1172/jci.insight.123775

Tian, W., Rockson, S. G., Jiang, X., Kim, J., Begaye, A., Shuffle, E. M., et al. (2017). Leukotriene B4 antagonism ameliorates experimental lymphedema. Science Translational Medicine, 9(389), eaal3920. http://doi.org/10.1126/scitranslmed.aal3920

Turner, J. D., Pionnier, N., Furlong-Silva, J., Sjoberg, H., Cross, S., Halliday, A., et al. (2018). Interleukin-4 activated macrophages mediate immunity to filarial helminth infection by sustaining CCR3-dependent eosinophilia. PLoS Pathogens, 14(3), e1006949–20. http://doi.org/10.1371/journal.ppat.1006949

Halliday, A., Guimaraes, A. F., Tyrer, H. E., Metuge, H., Patrick, C., Arnaud, K.-O., et al. (2014). A murine macrofilaricide pre-clinical screening model for onchocerciasis and lymphatic filariasis. Parasites & Vectors, 7(1), 472. http://doi.org/10.1186/s13071-014-0472-z

Ventura, G., Calvano, C.D., Porcelli, V., Palmieri, L., De Giacomo, A., Xu, Y., Goodacre, R., Palmisano, F. & Cataldi, T.R.I. (2020) Lipidomics of human blood lymphocytes: the tricky case of children affected by Autism Spectrum Disorder (ASD) and their healthy siblings.  Analytical and Bioanalytical Chemistry 412, 6859-5874.

Deadline: Thursday 11th February 2021; 12:00 noon GMT

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