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 263M cases in 2023, of which 597k were fatal. Whilst there are two vaccines available, their efficacy is variable in areas with high risk of malaria and weans off 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 also contribute to protection from liver stage malaria, upon recognising a novel, vitamin B2-biosynthesis independent antigen [unpublished]. We now seek to further characterise the mechanisms involved in MAIT responses to liver-stage P. falciparum infection, in the context of a liver-cell based assay.
Objectives and approaches:
Aim (i): Explore the response of primary blood
MAIT cells to P. falciparum infected hepatocyte cell using flow cytometry and cytometric bead array.
Aim (ii): Characterise MR1 and co-stimulatory requirements for MAIT cell activation by
P. falciparum infected liver cells using CRISPR, flow cytometry, and cytometric bead array.
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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