Plasmodium infection-induced perturbation of the B cell compartment of the bone marrow and its impact on malaria immunity
Many pathogens, such as Plasmodium, Mycobacterium tuberculosis (Mtb), HIV, Leishmania and Trypanosoma disseminate and persist in the bone marrow (BM). This poses a conundrum given our current understanding of central tolerance, according to which developing B lymphocytes that bind cognate antigen with high affinity in BM, are deleted from the lymphocyte repertoire or rendered anergic to prevent autoimmunity.
Approximately 250 million cases of malaria occur each year, claiming the lives of over 500,000 children in Africa alone. Natural immunity to Plasmodium falciparum malaria develops slowly and malaria vaccine trials have been disappointing, with low efficacy and poor longevity, particularly in areas with high malaria exposure.
I plan to investigate whether pathogen presence in the BM drives negative selection or anergy in pathogen-specific developing lymphocytes. This would lead to tolerance to the pathogen and could contribute to inefficient acquisition of natural and vaccine-induced immunity that has been observed for many of the pathogens that persist in the BM. Testing this hypothesis, I am working with murine malaria models and human PBMCs in collaboration with malaria-endemic field sites in Mali and Ghana. Proposed approaches include next-generation sequencing of the immune repertoire, cellular immunology and 10X genomics RNAseq. Illuminating how malaria-induced lymphopoietic disturbances contribute to poor acquisition of immunity, this work is of broad relevance to a wide range of pathogens that are known to persist in the BM and for which effective vaccines have thus far been elusive.