Longitudinal analysis of Plasmodium falciparum-specific atypical and classical memory B cell responses to natural malaria infection in children and adults

Abstract

Abstract Antibodies play a key role in naturally acquired immunity to malaria; however, protective antibodies are only acquired after years of repeated Plasmodium falciparum (Pf) infections. We have shown in Mali that this inefficiency in humoral immunity to malaria is associated with an expansion of CD21loCD27− ‘atypical’ MBCs that are isotype-switched and somatically hypermutated, but that exhibit markedly reduced effector functions. A similar subset of ‘exhausted’ MBCs has been observed in patients with chronic viral infections. However, in the context of malaria, it remains unclear whether atypical MBC expansion is Pf-specific or represents a global expansion as a result of chronic immune activation from repeated Pf infections and/or co-infections common in malaria-endemic areas. Using PfMSP1/PfAMA1 B cell tetramer staining we recently identified an expanded population of Pf-specific MBCs in malaria-exposed individuals that were 60 fold more frequent as compared to healthy U.S. adults. Preliminary findings show that monoclonal antibodies expressed from PfMSP1-specific MBCs are indeed PfMSP1-specific by ELISA. Using this B cell tetramer approach, we are tracking Pf-specific classical and atypical MBCs in a longitudinal cohort study of children and adults in Mali. With tetramers specific for tetanus and influenza we will determine the relative role of Pf in driving atypical MBC expansion by comparing the Pf-, tetanus-and influenza-specific MBC responses from age 3 months to 25 years before, during and after an acute Pf infection. This analysis should provide new insights into the mechanisms underlying the delayed acquisition of immunity to malaria in children, and may aid in the development of an urgently needed malaria vaccine.