Abstract
BackgroundAntibodies that protect against Plasmodium falciparum (Pf) malaria are only acquired after years of repeated infections. The B cell biology that underlies this observation is poorly understood. We previously reported that “atypical” memory B cells are increased in children and adults exposed to intense Pf transmission in Mali, similar to what has been observed in individuals infected with HIV. In this study we examined B cell subsets of Pf -infected adults in Peru and Mali to determine if Pf transmission intensity correlates with atypical memory B cell expansion.Methodology/Principal FindingsIn this cross-sectional study venous blood was collected from adults in areas of zero (U.S., n = 10), low (Peru, n = 18) and high (Mali, n = 12) Pf transmission. Adults in Peru and Mali were infected with Pf at the time of blood collection. Thawed lymphocytes were analyzed by flow cytometry to quantify B cell subsets, including atypical memory B cells, defined by the cell surface markers CD19+ CD20+ CD21− CD27− CD10−. In Peru, the mean level of atypical memory B cells, as a percent of total B cells, was higher than U.S. adults (Peru mean: 5.4% [95% CI: 3.61–7.28]; U.S. mean: 1.4% [95% CI: 0.92–1.81]; p<0.0001) but lower than Malian adults (Mali mean 13.1% [95% CI: 10.68–15.57]; p = 0.0001). In Peru, individuals self-reporting ≥1 prior malaria episodes had a higher percentage of atypical memory B cells compared to those reporting no prior episodes (≥1 prior episodes mean: 6.6% [95% CI: 4.09–9.11]; no prior episodes mean: 3.1% [95% CI: 1.52–4.73]; p = 0.028).Conclusions/SignificanceCompared to Pf-naive controls, atypical memory B cells were increased in Peruvian adults exposed to low Pf transmission, and further increased in Malian adults exposed to intense Pf transmission. Understanding the origin, function and antigen specificity of atypical memory B cells in the context of Pf infection could contribute to our understanding of naturally-acquired malaria immunity.
Highlights
Passive transfer studies in humans indicate that antibodies (Abs) play a critical role in controlling the disease associated with the asexual blood stages of Plasmodium falciparum (P f) malaria [1,2]
To gain further insight into the relationship between atypical memory B cells (MBCs) and Plasmodium falciparum (Pf) infection we examined by flow cytometry the B cell subsets of Pf -infected adults in Peru and Mali, and Pf-naive adults in the U.S The specific objectives of this study were to determine if atypical MBC expansion is an observation that can be generalized to Pf-exposed individuals in Peru, and if there is a correlation between the degree of atypical MBC expansion and Pf transmission intensity
We observed that atypical MBCs were expanded in Pf-infected individuals in Peru relative to Pf-naive individuals, and that the degree of atypical MBC expansion increased with increasing Pf transmission intensity
Summary
Passive transfer studies in humans indicate that antibodies (Abs) play a critical role in controlling the disease associated with the asexual blood stages of Plasmodium falciparum (P f) malaria [1,2]. Abs that protect against clinical malaria are only acquired after repeated infections and may be relatively short-lived [3,4] This stands in contrast to the long-term or even lifelong Abmediated immunity that follows one or a few exposures to many viral and bacterial antigens, either through natural exposure or vaccination [5]. Several studies suggest that high-affinity antigen binding drives naıve B cells to differentiate into short-lived, isotypeswitched plasma cells (PCs) within the extra-follicular region which contributes to the initial control of infections. LLPCs migrate to the bone marrow where they constitutively secrete antibody and provide a critical first line of defense against re-infection, whereas MBCs recirculate and mediate recall antibody responses after reexposure to their cognate antigen by rapidly proliferating and differentiating into PCs. Antibodies that protect against Plasmodium falciparum (Pf) malaria are only acquired after years of repeated infections. In this study we examined B cell subsets of Pf -infected adults in Peru and Mali to determine if Pf transmission intensity correlates with atypical memory B cell expansion
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