Project Details
Projekt
The impact of malaria and EBV on germinal center dynamics in the pathogenesis and evolution of endemic Burkitt lymphoma
Subject Area
Hematology, Oncology
Term
since 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 518442780
Coinfection with Plasmodium and EBV is essential for the pathogenesis of endemic Burkitt lymphoma (eBL), but the underlying molecular and cellular mechanisms contributed by each pathogen, are barely understood. Our preliminary data suggest that Plasmodium infection interferes with follicular helper T (Tfh) cell functions, thereby perturbing the germinal center (GC) environment. EBV provides a pro-survival effect to infected GC B cell clones, directly via the expression of molecules like the latent membrane protein 2A (LMP2A), but potentially also indirectly by interfering with GC B cell-Tfh cell selection processes. We assume that the coinfection with both pathogens can cause a premalignant condition, in which GC B cell (oligo-)clones expand independent of negative selection processes and independent of antigen clearance. Furthermore, as both infectious agents have been described to increase AID-mediated mutagenesis, we hypothesize that each pathogen influences the competition and evolution of pre-malignant clones until terminal transformation into eBL, e.g., upon MYC translocation. To investigate this, we will extend our analysis of Tfh cells and GC B cells at different timepoints during P. yoelii infection or SRBC immunization of WT mice and LMP2Atg mice to mimic EBV latency. Longitudinal BCR/TCR repertoire sequencing will be used to reveal the dynamics of clonal selection and outgrowth in the different experimental conditions, and RNA sequencing and functional analyses shall give insight into the deregulated pathways underlying the prolonged and perturbed GC reactions. The essential role of Tfh cells in eBL premalignancy will be confirmed by a conditional inducible Tfh cell knockout model. Finally, we aim to foster eBL lymphomagenesis by conditional MYC overexpression in GC B cells and determine the impact of Plasmodium- and/or EBV-(co)-infection on the growth dynamics and investigate the mutational landscape of developing eBL tumors in the different mouse models by exome sequencing.
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