Last Updated: 28/08/2024
Investigating the molecular mechanisms of Plasmodium vivax invasion in Duffy-negative hosts
Objectives
This proposal aims to understand the mechanisms that govern Plasmodium vivax Duffy negative invasion through a dual in vitro and in vivo approach, utilizing cutting edge genomics and computational tools to understand the molecular mechanisms of Duffy-negative invasion at the single cell level.
While there have been significant gains in malaria control, mainly focusing on Plasmodium falciparum (Pf), Plasmodium vivax (Pv) has been expanding to fix the niche left behind. This phenomenon could be due to the formation of dormant liver forms, called hypnozites, sequestration in extravascular spaces, and early mosquito transmission of sexual staged parasites. Pv was thought to be absent from Africa due to the high prevalence of Duffy- negativity, an antigen on human erythrocytes that was thought to be required for Pv infection. There has been a paradigm shift in this belief due to multiple reports of Duffy-negative invasion throughout the African continent. Despite these reports, there has not been a definitive invasion pathway identified for Pv that facilitates Duffy-negative invasion. By investigating Pv invasion utilizing an in vitro model inhibited by invasion blocking monoclonal antibodies, a novel line of Plasmodium knowlesi that can invade Duffy-negative erythrocytes, and single cell RNA sequencing (scRNAseq) (Aim 1), we will identify invasion pathways that are upregulated to facilitate alternative invasion pathways at the level of the malaria cell cycle stage. This project will validate these pathways through isolating Pv samples from an ongoing study in Duffy-positive and Duffy-negative individuals (Aim 2). This work will provide key insights into Pv pathogenesis that will inform malaria control strategies and public health interventions globally. In addition to the scientific training the trainee will gain, he has organized a group of scientific and clinical mentors that will guide his professional development to become a unique clinical scientist at the intersection of infectious disease and maternal health. His training in bioinformatics, clinical practice, and global health research will allow for gains in the understanding of the immense clinical burden of infectious disease in pregnancy, specifically malaria in pregnancy, and a foundational education in his career as a physician scientist.
Apr 2024 — Mar 2029
$39,238
