| Abstract | Lymphatic filariasis (LF) is a filarial nematode infection of medical importance. Due to the disabling and stigmatising morbidities invoked by LF (elephantiasis and hydrocele) and associated mental illness, this neglected tropical diseases is prioritised for elimination via annual mass drug administration (MDA) treatments. MDA does not halt the progression of pre-established LF clinical disease, and with 800 million individuals still at risk of infection, at least 40 million currently affected LF patients will endure a lifetime of progressively worsening disability. By modelling lymphatic filariasis pathology, we have determined a mechanistic role for ‘type-2’ allergic inflammation in mediating lymphatic disease. Within this in vivo preclinical model approach, we also have established that multiple polyunsaturated fatty acid derived bioactive lipids are highly elevated in infected lymphatic tissue and in circulation. Pilot data also suggests anti-inflammatory interventions disrupting the biosynthesis of these bioactive lipids can ameliorate filarial lymphatic disease, implying potential to be a therapeutic target to treat LF morbidities. In this project, embedded within a multi-disciplinary MRC Programme awarded to the supervisory team (Filariasis Lipids in Pathogenesis; FLiP), you will investigate the immune cellular sources of bioactive lipids during the course of experimental filarial infection and their roles in pathogenesis induction. Some potential objectives of the project are to: 1. Compare circulating bioactive lipidomes upregulated during experimental or clinical filariasis 2. determine host cellular sources of bioactive lipids during experimental infection 3. investigate consequences of bioactive lipid exposure to human lymphatic endothelium 4. examine the functional consequences of bioactive lipid production in specific immune cells via targeted tissue-specific loss of function 5. interrogate whether functional ablation of different immune cells modifies disease outcomes |
| Where does this project lie in the translational pathway? | T1 - Basic Research,T2 - Human /Clinical Research |
| Expected Outputs | As part of FLiP, we have established a ~100-plex quantitative bioactive lipid liquid chromatography (LC) tandem mass spectrometry (MS-MS) system at The Centre for Metabolomics Research, University of Liverpool. The candidate will be trained to extract lipids from biological samples and run LC-MS/MS experiments with the FLiP scientific team to collect fully quantitative lipidomic data on bioactive lipid changes. The candidate will also be trained in quantitative flow cytometry, cell sorting, multiplex immuno-assay, focussed transcript arrays (e.g. NanoString), and immunoblotting in order to comprehensively research biological sources of bioactive lipid production and functional consequences on type-2 immunopathology. |
| Training Opportunities | Liquid chromatography mass spectrometry of target lipids, as well as for general lipid profiling Filarial parasitology including preclinical infection model (whole animal physiology) Cellular immunology RNAseq or other transcriptomic approaches immunoblotting Computational analyses of focused lipidomic data sets such as hierarchical clustering, principal components analysis and binary logistic regression statistical analyses The student will also be trained in multicolour spectral flowcytometry and cell sorting techniques at LSTM. |
| Skills Required | As the project is multidisciplinary in nature, this would suit a talented biologist with interests and experience in infection biology and/or biochemistry. |
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Key Publications associated with this project |
Furlong-Silva J, Cross SD, Marriott AE, Pionnier N, Archer J, Steven A, Merker SS, Mack M, Hong YK, Taylor MJ, Turner JD. Tetracyclines improve experimental lymphatic filariasis pathology by disrupting interleukin-4 receptor-mediated lymphangiogenesis. J Clin Invest. 2021 Mar 1;131(5). doi: 10.1172/JCI140853. PubMed PMID: 33434186; PubMed Central PMCID: PMC7919730. |
| 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 | |
| Sinclair E, Trivedi DK, Sarkar D, Walton-Doyle C, Milne J, Kunath T, Rijs AM, de Bie RMA, Goodacre R, Silverdale M, Barran P Metabolomics of sebum reveals lipid dysregulation in Parkinson's disease. Nat Commun. 2021 Mar 11;12(1):1592. doi: 10.1038/s41467-021-21669-4. |