Reprogramming human T cells for disease tolerance in falciparum malaria

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Malaria parasites are spread by mosquitoes and kill hundreds of thousands of children each year. Efforts to control malaria are focussed on stopping mosquitoes from biting (by spraying insecticides and sleeping under bednets) and reducing parasite numbers in the blood (using drugs or the recently licensed, partially effective malaria vaccine). Unfortunately, none of these interventions are 100% effective in protecting children from becoming infected. When they do, their risk of developing life-threatening complications is high, since severe malaria is most common during the first infection of life. The problem is exacerbated by the emergence of insecticide-resistant mosquitoes and drug-resistant parasites as well as quickly waning vaccine-induced immunity.However, we know that children who survive their first infection quickly develop immunity against severe forms of the disease - even if they are reinfected with the same or greater numbers of parasites. Immunity to severe malaria is thus not dependent on the immune system being able to kill parasites, but is instead underpinned by its ability to tolerate their presence and limit the damage the infection causes. Understanding how tolerance works in malaria would thus allow us to complement existing exposure control measures with a completely different strategy of host defense aimed at protecting the most vulnerable age-group from dying from severe malaria.Since it is impossible in the field to pinpoint when exactly a child is infected for the first time, we have started to study tolerance using an experimental medicine approach: healthy adult volunteers are infected with malaria parasites under safe controlled conditions three times over the course of a year. When analysing the blood samples collected, we have found that volunteers do not get any better at killing malaria parasites - despite being infected with the same clone. Volunteers also continue to experience very high levels of inflammation driving hallmark symptoms of malaria like fever. Crucially though, we have found that during first infection T cells, which are key orchestrators of the immune response, are indiscriminately activated. Furthermore there was clear evidence of liver injury indicating wide-spread damage of host tissue. In contrast, during reinfection T cell activation was dramatically reduced and no collateral tissue damage was observed.In this programme of work we are proposing to resolve the mechanism of T cell tolerance in human volunteers taking part in this experimental rechallenge model of malaria by addressing the following critical questions: [1] are activated T cells causing the tissue damage we observe in first infection? [2] how are these T cells switched off during reinfection? [3] does switching off the majority of T cells prevent you from developing anti-parasite immunity? [4] does malaria-induced tolerance suppress other immune responses (such as to vaccines)? To answer these questions we will push the boundaries of controlled human malaria infection by incorporating yellow fever vaccination (to track the fate of virus-specific T cells during malaria), giving our volunteers heavy water to drink (which marks T cells activated by infection) and exploring the biggest pool of T cells in the human body - the bone marrow. By understanding how tolerance is acquired (and whether there are any detrimental consequences) we will for the first time be able to harness the power of this defense strategy to ensure children survive malaria.