Project: Establishing a human liver-like assay for MAIT cell responses to liver stage malaria
Eckle Group
Malaria is caused by species of the protozoan parasite genus Plasmodium, such as P. falciparum. It remains one of the deadliest infectious diseases worldwide, with an estimated 247M cases in 2021, of which 619k were fatal. Whilst there are two vaccines available, their efficacy is suboptimal in areas with high risk of malaria and diminishes quickly. Hence, there is a need for malaria vaccines that induce high levels of sustained protection, informed by a deeper understanding of the mechanisms that induce protective immunity.
Mucosal-Associated Invariant T (MAIT) cells are a subset of innate-like T cells which make up on average 20-50% of T cells in human liver. It is well established that MAIT cells contribute to protection from bacterial and fungal infections [1]. This involves MAIT cells recognising a modified precursor of vitamin B2-biosynthesis found in many bacteria and fungi [2]. We recently found that MAIT cells can contribute to protection from liver stage malaria and recognise a novel vitamin B2-biosynthesis independent antigen We now seek to develop an in vitro assay that mimics MAIT cell responses to liver stage malaria as they occur in the human liver.
Objectives and approaches.
Aim (i): Characterise co-stimulatory signals contributing to MR1-antigen dependent MAIT cell activation by liver stage malaria parasites using CRISPR, cytometric bead array and flow cytometry.
Aim (ii): Assess the capacity of a range of liver cell lines and primary liver cells as well as liver MAIT cells to respond to liver stage malaria.
References
[1] Provine NM, Klenerman P. MAIT Cells in Health and Disease. Annu Rev Immunol. 2020.
[2] Corbett AJ, Eckle SB, Birkinshaw RW, Liu L, Patel O, Mahony J, Chen Z, Reantragoon R, Meehan B, Cao H, Williamson NA, Strugnell RA, Van Sinderen D, Mak JY, Fairlie DP, Kjer-Nielsen L, Rossjohn J, McCluskey J. T-cell activation by transitory neo-antigens derived from distinct microbial pathways. Nature. 2014;509:361-5.
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Eckle Group
2 vacancies
The Eckle group is interested in understanding the role of MAIT cells in diverse infectious diseases. We are also interested in understanding the mechanisms that drive MAIT cell function with a particular focus on the discovery of antigens and their recognition by MAIT cell receptors. Our long-term vision is to harness MAIT cells for immunotherapies and vaccines. In collaboration with Dr Catarina Almeida we are also interested in understanding the molecular mechanisms of T cell mediated hypersensitivities involving both conventional and unconventional T cells (MAIT cells and CD1 restricted T cells). We study unconventional T cell responses using flow cytometry and RNA sequencing in mouse models, human blood and tissues and human reporter cell lines, and use a range of biochemical techniques for antigen discovery.
Eckle Group Current Projects
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Understanding the role of conventional and unconventional T cells (MAIT cells and CD1-restricted T cells) in allergies
PhD/MPhil, Master of Biomedical Science, Honours
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Understanding the role of MAIT cells in diverse parasitic infections
PhD/MPhil, Master of Biomedical Science, Honours
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Determining the role of MAIT cells in blood stage malaria
PhD/MPhil, Master of Biomedical Science, Honours
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Establishing a human liver-like assay for MAIT cell responses to liver stage malaria
PhD/MPhil, Master of Biomedical Science, Honours
Research degrees at the Doherty Institute are administered by the University of Melbourne.