Reprogramming human T cells for disease tolerance in falciparum malaria

Immunity to malaria is a two-step process. First, individuals acquire protection against severe life-threatening disease (often before 12-months of age) and then after many years of exposure protection against febrile malaria is established, which promotes the transition to asymptomatic infection. Immunity to febrile malaria coincides with control of parasite burden (and is therefore supported by mechanisms of host resistance) whereas immunity to severe malaria is acquired independently of pathogen load and is a form of disease tolerance. All current malaria control programmes are designed to minimise exposure or promote host resistance; breakthrough infections can therefore lead to severe disease. If the mechanisms that underpin disease tolerance can be elucidated it may be possible to implement additional control measures that are specifically designed to reduce malaria mortality. In 2018 a human rechallenge model of falciparum malaria was developed to track the development of disease tolerance in real-time in a clinical setting. The data indicates that reprogramming of adaptive T cells to minimise collateral tissue damage and the harm caused by parasite sequestration underpins immunity to severe malaria. Specifically, this study will interrogate T cell activation and pathogenicity during a first-in-life infection; ask whether T cell reprogramming is protective upon rechallenge; and determine whether disease tolerance requires cell-intrinsic modifications or tissue remodelling. Importantly, It will also ask whether tolerance has any long-term fitness costs, such as delaying host resistance mechanisms or suppressing immune responses to heterologous antigens or vaccines. Collectively, these experiments can provide a clear path to control programmes that promote tolerance to reduce mortality.

Project Details

Basic Science
Vaccines (Immune Correlates)

Dec 2022 — Nov 2027

$2.55M

United Kingdom