Role of TAM receptors in modulating humoral immunity against parasitic infections

ABSTRACT Unlike many infectious diseases, naturally acquired immunity against Plasmodium do not represent durable sterilizing immunity. While the gradual acquisition of protective or clinical immunity following repeat infections is a solace for people living in endemic regions, these symptom-less carriers become critical reservoirs of the

pathogen, facilitating inadvertent transmission. The overarching goal of our research program is to identify molecular and cellular immune mechanisms and targets that are in play during the pathogenesis of malaria resulting in suboptimal immune response that fails to induce sterilizing immunity and to devise

immunomodulatory host-directed interventions against this life-threatening disease. Our recent observations point towards some key pathophysiological features of the disease contributing to this dysregulated and suboptimal induction of humoral immune response. This project revolves around the central hypothesis that

systemic hypoxia subsequent to malaria-induced hemolytic anemia induces the expression of TAM receptors on B cells to drive the accumulation of extrafollicular plasmablasts, that in turn exercise an immunosuppressive function by acting as a nutrient sink. This proposal employs a combination of genetic, biochemical and bone

marrow chimeric approaches to investigate the potential of interrupting the hypoxia-TAM receptors(s)- plasmablast-nutrient sink axis to improve the overall quality and magnitude of anti-Plasmodium humoral immune response. In this proposal we also plan to repurpose an immunostimulatory drug, in stage 2 clinical trials that

block AXL, one of the TAM receptors and to investigate how AXL deficiency/blockade may reprogram Plasmodium specific germinal center B cells by inducing transcriptional and epigenetic changes. By successfully completing the experiments proposed in this project, we hope to discern (i) the precise mechanism by which

TAM receptor govern the differentiation of plasmablasts (ii) how the pathophysiology of the disease (such as anemia) itself can alter the immune landscape and (iii) the different interventions to optimize the immune response to harness its full potential.