mTOR control of effector CD4+ T cell activation during malaria infection

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Malaria infection remains a significant cause of morbidity and mortality in humans in many regions of the world. At present we still do not fully understand why some individuals are protected from severe malarial disease, symptoms of which include respiratory distress, anaemia and cerebral pathology, and why others, in particular young children, pregnant women and semi-immune adults, are very susceptible to infection. Accumulating evidence, however, suggests that many of the severe complications of infection are not caused directly by the parasite itself but are, in large part, determined by the way an individual responds to the parasite and the nature of the immune response that they develop. An individual that mounts a very strong pro-inflammatory immune response to the parasite appears to be at much higher risk of developing severe malarial disease than an individual who mounts a lower inflammatory response. Strong pro-inflammatory immune responses within sensitive areas of the body may lead to organ damage and in extreme cases, death. Successful resolution of malaria (and many other) infections appears to depend upon allowing a sufficient immune response to develop to kill parasites, but then suppressing these responses before they become too strong and cause tissue damage. How the body identifies the correct time during infection to dampen the inflammatory response to the parasite, and the ways through which inflammatory cells are instructed to become less inflammatory, are poorly understood. In this proposal we aim to address how a specific population of immune cells, called effector CD4+ T cells, which can produce copious amounts of pro-inflammatory mediators and directly cause tissue damage during malaria infection, are regulated. It is now known that CD4+ T cells need to generate huge amounts of energy through processing glucose and amino acids (a process called metabolism) to cause inflammation whereas CD4+ T cells that are less inflammatory require far less energy. Effector CD4+ T cell metabolism is largely controlled by the mammalian target of Rapamycin (mTOR) complex, which is located inside the CD4+ T cell. Crucially, we have shown that mTOR is highly activated in CD4+ T cells during the early stages of malaria infection, suggesting that mTOR promotes effector CD4+ T cell activation but is less active in CD4+ T cells during the latter stages of infection. Thus, our data suggests that effector CD4+ T cell metabolism and mTOR activity is downregulated during the course of malaria infection and that this may be a major reason for the reduction in the ability of CD4+ T cells to cause inflammation. In this project we will investigate in detail using a spectrum of techniques the metabolic profile of CD4+ T cells during the course of malaria infection and we will address the functional importance of mTOR and related pathways in determining effector CD4+ T inflammatory function. Subsequently we will modify effector CD4+ T cell metabolism at various stages of malaria infection and assess the impact of this on the control of malaria infection. Finally, we will identify the various immunological signals that modify mTOR activation and effector CD4+ T cell metabolism during malaria infection. Our project will provide the first integrated overview of how CD4+ T cells simultaneously respond to their environment and immunological signals during malaria infection. The results from this project will significantly increase our understanding of how pro-inflammatory immune responses are regulated during malaria infection. This knowledge should lead to more accurate prognosis of individuals at risk of severe disease but should also inform the development of adjunct therapies that can be used to treat individuals with severe malaria. We expect that our findings will also be directly relevant to the understanding and treatment of many other acute infectious diseases.