The CD4+ T cell memory in Plasmodium falciparum malaria

• Applicant: Dr. Maria Sophia Mackroth
• Subject Area: Clinical Infectiology and Tropical Medicine ; Immunology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 460760753

Natural immunity to Plasmodium falciparum (Pf) malaria takes many years to develop and is mainly mediated by antibodies and a Th1 type CD4+ T cell response directed to the blood-stage of malaria. Data from endemic areas indicate that natural immunity is short-lived and requires regular exposure. Malaria vaccine candidates also show reduced efficacy in endemic areas. In contrast to these observations, experimental malaria infections or vaccinations of volunteers in Europe induce robust T and B cell responses which remain stable > 12 months. This raises the question of how natural infections with Pf interfere with the acquisition of long-term immunity. The overall aim of our study is to identify mechanisms which influence the induction of long-lived CD4+ T cell memory to malaria and could be targeted to improve long-term persistence. One important difference between patients with acute malaria and experimentally infected volunteers is the degree of CD4+ T cell activation and regulation. Patients with acute malaria show strong pro-inflammatory T cell responses and the activation of several counterregulatory mechanisms to limit the inflammation, in particular the expression of coinhibitory molecules. Experimentally infected volunteers, on the other hand, are commonly treated at a very low parasitaemia and therefore do not develop strong T cell activation nor -regulation. We hypothesize that the massive induction of coinhibitory molecules during the natural course of malaria inhibits the development of a long-lived T-cell memory response to the blood-stage of malaria. To this end we will study the Pf-specific immune responses in patients with acute malaria in Hamburg over the course of 12 months. We will compare the memory responses of individuals with high and low expression pattern of coinhibitory molecules by comparing patients with acute malaria to individuals from controlled human malaria infection trials. Firstly, we will conduct a comprehensive analysis of the T effector cell response during acute malaria. Secondly, we will follow patients over 12 months and assess Pf-specific memory T cell responses in a disease-free interval, using ELISPOT, multicolour FACS and intracellular cytokine analysis as well as single cell and bulk T cell receptor sequencing. We will test if the blockade of coinhibitory molecules can enhance Pf-specific memory responses. Thirdly, we will correlate the longevity of T cell responses and the extend of contraction with the parameters acquired during acute disease in order to identify immunological correlates for the memory development. Overall, this project will answer basic questions on CD4+ T cell memory induction in malaria and acute infections in general, of which surprisingly little is known. We aim to identify mechanisms that interfere with the induction of a long-lasting CD4+ T cell memory in malaria and could be modified in vaccine design and -trials to develop effective malaria vaccines for endemic areas.

• DFG Programme: Research Grants