Award details

The Effect Of Malaria Parasites On Dendritic Cell Metabolism (TEMPODM)

Reference	BB/X00029X/1
Principal Investigator / Supervisor	Professor James MacDonald Brewer
Co-Investigators / Co-Supervisors	Professor Albena Dinkova-Kostova
Institution	University of Glasgow
Department	College of Medical, Veterinary, Life Sci
Funding type	Research
Value (£)	480,137
Status	Current
Type	Research Grant
Start date	01/04/2023
End date	31/03/2026
Duration	36 months

Abstract

Children in malaria endemic regions have weakened immune responses against immune challenges, such as infections, childhood vaccines and vaccines against malaria. Within the immune system, dendritic cells (DC) direct the on/off decision of the adaptive immune system. Our previous studies place DC at the centre of the effects of malaria on adaptive immunity. These have shown that malaria-infected red blood cells (iRBCs) render DC incapable of T cell activation, subsequent proliferation and differentiation, thus leading to weakened adaptive immune responses. The preliminary data in this application demonstrates that DC exposed to iRBC undergo significant changes in intracellular organisation, and most strikingly, damage to mitochondria. This latter effect is associated with loss of mitochondrial membrane potential and widespread metabolic changes. However, the DC remain viable and show induction of anti-ferroptosis strategies controlled by the transcription factor, NRF-2. Based on these studies, we hypothesise that iRBC induce early ferroptosis pathways in DC, and that this process or subsequent metabolic adaptation responses via NRF2, render DC incapable of activating T cells. We will address this hypothesis by identifying approaches to manipulate the key metabolic pathways in DC that are affected by iRBC. We will then examine the effect of manipulating DC metabolism on functional immune responses in vivo, in particular, the DC interaction with, and activation of, T cells. We propose that drugs that can block alterations in these metabolic processes or their downstream effectors could restore immune function and therefore overcome malaria induced immune suppression.

Summary

Children in malaria endemic regions have weakened immune responses against immune challenges, such as infection or childhood vaccines. This poses a particularly significant problem for malaria vaccines, which have been much less successful in malaria exposed, compared with non-exposed (western) populations. Research by our team, and others, has led to the hypothesis that malaria blocks the physical interaction of two key immune cells, T cells and Dendritic Cells (DC). The interaction of T cells with DC is essential to form a protective immune response to infections or vaccines. To understand why this happens, we found that when malaria parasites are eaten by DC they damage the key generators of cellular energy, called mitochondria. While this should cause DC to die, we have shown that DC adapt by using other energy generating approaches to stay alive. We believe that this loss of power, or the adaptation process resulting from this, produces the failure in DC function during malaria infection. These processes are also of interest to cancer researchers, as an important way for tumour cells to stay alive, as a result, there are many drugs available to interfere with these processes. We can therefore use these drugs as tools to understand which aspects of adaptation are important in loss of DC function, and whether these allow T/DC interactions to proceed. Finally, we hypothesise that identifying drugs that can re-establish T cell/DC interactions in the face of malaria can be used enhance protective vaccination in malaria endemic regions.

Committee	Research Committee D (Molecules, cells and industrial biotechnology)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

I accept the terms and conditions of use (opens in new window)

export PDF file

back to list new search