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. Our research investigates 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. Using human samples from a malaria-endemic region in Mali, as well as a chronic malaria mouse model, experimental approaches involve cellular immunology, immunofluorescence analysis and next-generation sequencing of the B cell receptor (BCR) repertoire. 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.

V(D)J recombination creates billions of antibodies (B cell receptors, BCRs) that collectively provide broad protection against a vast diversity of pathogens. The antibody repertoire is further diversified through somatic hypermutation (SHM). Quantification of this diversity has been possible since the recent development of high-throughput immune repertoire sequencing. Many studies have examined how the BCR repertoires change in response to vaccination or infection, yet few have explored the longitudinal evolution and dynamics of the immune repertoire in healthy individuals. Using a unique set of samples obtained from an ongoing longitudinal cohort study in malaria-endemic Mali, we are characterizing the BCR repertoires as they evolve over the course of many years, assessing the impact of successive acute malaria episodes and generating key insights into the longevity of malaria-specific B cell clones.

The work with cohort studies in Mali is conducted through a close collaboration with Peter Crompton's laboratory at NIAID/NIH, an experienced team of clinicians and scientists from the Malaria Research and Training Center (MRTC) at the University of Bamako, and the support provided by the NIAID International Centers for Excellence in Research (ICER) program.