Plasmodium infection-induced perturbation of the lymphopoietic compartment of the bone marrow and its impact on malaria immunity

• Applicant: Dr. Christine Hopp, Ph.D.
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 490906995

Natural immunity to malaria develops slowly and malaria vaccine trials have been disappointing, with low efficacy and poor longevity, particularly in areas with high malaria exposure. Many pathogens (Malaria, Leishmania, Trypanosoma, Mycobacterium tuberculosis (Mtb) and HIV) can persist in the human and murine bone marrow (BM), where B lymphocytes develop. As they mature, B cells that bind to molecules present in this environment undergo negative selection and are deleted from the repertoire to prevent autoimmunity. The proposed research will investigate the hypothesis that through persistence in the BM, pathogens can exploit this endogenous mechanism for self-tolerance. This would lead to pathogen-specific tolerance and could contribute to inefficient acquisition of natural and vaccine-induced immunity. The planned research will investigate whether persistence of malaria parasites phenotypically alters the population of B cells that are newly emerging from the BM and whether pathogen persistence in the lymphopoietic compartment of the BM leads to negative selection of pathogen-specific developing B cells. These research questions will be addressed both with human samples from malaria-endemic regions (Mali/Ghana), and a chronic malaria mouse model. Experimental approaches involve cellular immunology and next-generation sequencing of the B cell receptor (BCR) repertoire of the population of newly emerging human peripheral B cells before/during asymptomatic infection, as well as BCR repertoire sequencing of BM-derived B cells before/during chronic infection in the malaria mouse model. Further plans include usage of BCR-transgenic mice to follow antigen-specific B cell development in mice infected with parasite lines expressing the model antigen. An additional question is whether asymptomatic parasite persistence in the BM leads to long-term global changes in the transcriptomes and cellular composition of the developing B cell population in the BM. This will be addressed using single cell transcriptomic profiling paired with BCR sequencing and CITE-Seq, for the identification of key stages in the developing B cell populations. To assess whether malaria induces long-term restructuring of the BM microenvironment of B cell development, immunofluorescence analysis will visualize developing B cells together with parasites. This research will generate the first data sets of the developing immune repertoire, as well as single cell transcriptomic assessment of the lymphopoietic compartment in the context of an infection, providing fundamental insights into host-pathogen interactions. It will be elucidated whether pathogen persistence in the BM can undermine efficient acquisition of immunity and illuminate underlying mechanisms, that will ultimately prove critical for the development of an effective vaccine against pathogens such as malaria, HIV and Mtb.

• DFG Programme: Research Grants
• International Connection: United Kingdom, USA
• Cooperation Partners: Dr. Peter Crompton, Ph.D.; Dr. Phil Spence, Ph.D.