ABSTRACT There is currently a lack of mechanistic understanding of why humoral immunity against malaria is not efficiently induced and why Plasmodium infections are associated immune failures, even following repeated infections. Our long-term goal is to determine how Plasmodium parasites, and potentially other protozoan infections, co-opt and subvert humoral immunity, which will help with the identification and development of new immune-based interventions against devastating diseases like malaria. The objectives of this project are to define mechanisms that trigger initial humoral immune dysregulation and study the consequences of these events on the formation of durable humoral immune memory. Our central hypothesis is that robust humoral immunity does not develop efficiently because polyclonal B cell activation events establish a nutrient sink that impairs the metabolic, transcriptional and epigenetic programming and function of Plasmodium-specific memory B cells. The rationale for this project is linked to our recent discovery that Plasmodium infection results in a massive polyclonal expansion of B cells that function as a nutrient sink that limits protective memory B cell responses. Deletion of these B cells accelerates blood-stage Plasmodium parasite clearance and enhances humoral immune memory. Supplementing the diet of infected mice with a single amino acid is sufficient to overcome the nutrient sink and metabolic constraints imposed by these B cells and results in enhanced humoral immune memory responses. Despite our new findings, the molecular mechanisms governing the activation and function of immunoinhibitory B cells and the impact of these cells on the affinity and longevity of memory B cells remain critical knowledge gaps in our quest to improve humoral immunity against malaria. Two Aims address these priority questions. In the first Aim we will determine the molecular and cellular mechanisms that govern the expansion of these immunosuppressive B cells and investigate whether these populations are relevant to other infections associated with dysregulated humoral immunity. In the second Aim we will investigate the molecular and cellular consequences of immunosuppressive B cell expansions on the genetic and epigenetic programming of memory B cells. We have developed several innovative new reagents that afford unprecedented resolution for the study anti-malarial humoral immunity. The significance of this project is directly linked to our new findings showing that pathophysiological changes that occur during Plasmodium infection durably imprints on B cell fate and function. Thus, determining how these pathways coordinately regulate polyclonal B cell activation, development and humoral immunity will be broadly important to those studying infectious disease immunology and vaccinology.

PROJECT NARRATIVE There is currently a lack of mechanistic understanding of why humoral immunity against malaria is not efficiently induced. This project will define mechanisms that trigger immune dysregulation during malaria and study the long-term consequences of these events. Determining the pathways that regulate the development and humoral immunity will be broadly important to the fields of infectious disease immunology and vaccinology.