Mechanisms and consequences of extrafollicular B cell activation during malaria

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.

Grant Number: 5R01AI167058-05
NIH Institute/Center: NIH
Principal Investigator: Noah Butler