Development and function of Plasmodium-specific memory B cells during blood stage malaria infection
Krishnamurty, Akshay Tilak
MetadataShow full item record
Humoral immunity to infection depends upon two layers of protection: pre-existing antibodies expressed by long-lived plasma cells and a stable population of rapidly reactive memory B cells (MBCs). If pre-existing antibody concentrations are not sufficient to control secondary infections, MBCs are poised to respond by rapidly producing antibody-secreting cells to help neutralize the invading pathogen. Classically defined MBCs are derived in a germinal center (GC) dependent fashion and express high-affinity class-switched, somatically hypermutated B cell receptors (BCR), making these cells the gold standard target of most vaccine platforms. Recent studies have expanded upon conventional MBC paradigms and it is now recognized that phenotypically and functionally heterogeneous MBCs have been described in mice and humans. Given the complexity of these processes, the development of a system to better visualize how endogenous populations of distinct MBC subsets form in response to complex infections will better elucidate their identity and function to inform novel vaccine strategies. In the studies presented here, we chose to focus on the development of the humoral immune response to Plasmodium, the causative agent of malaria. The major roadblock to an effective malaria vaccine is our limited understanding of the cellular mechanisms that lead to long-lasting immunity against the Plasmodium parasite. B cells are known to be critical mediators of immunity against blood stage malaria infection but little is known about the development, function or maintenance of malaria-specific MBCs. To gain insight into the types of MBCs that form and function during primary and secondary Plasmodium infection, we developed a novel B cell tetramer against the Plasmodium protein Merozoite Surface Protein 1 (MSP1). Using this approach in mice, phenotypically and functionally heterogeneous subsets of MSP1-specific MBCs form and persist for at least a year after control of parasitemia. Long-lived murine MSP1-specific MBCs consisted of three populations: GC-dependent, somatically hypermutated IgM+ (defined as CD73+CD80+IgMhighIgDlow) and IgG+ (CD73+CD80+IgG+) MBC subsets and an unmutated, GC-independent IgD+ (CD73-CD80-IgMlowIgDhigh) MBC population. Remarkably, somatically hypermutated MSP1-specific IgM+ MBCs outcompete IgG+ MBCs early during a secondary challenge resulting in the expansion of newly formed plasmablasts and increased levels of serum MSP1-specific IgM antibodies. Analyses of Plasmodium-specific B cells in malaria-infected individuals from endemic areas also revealed the presence of mutated IgM+ and IgG+ MBCs, substantiating the relevance of these cells in humans. Our studies provide the first glimpse of how memory B cells contribute to anti-Plasmodium immunity and highlight a previously unrecognized role for IgM+ MBCs during infection. We believe the findings from these studies will significantly enhance our understanding of how to develop a malaria vaccine that can provide long-lasting protection as well as provide novel insights into memory B cell biology in the context of infection.
- Immunology