Plasmodium vivax infection, the main cause of malaria in Latin America and Asia, affects 14.3 million people annually, with 3.3 billion people at risk worldwide. Individuals are repeatedly infected due to relapses from dormant liver forms or reinfection, with a major impact on wellbeing and socioeconomic development. No effective vaccine is available. P. vivax entry into red blood cells (RBCs) requires sequential ligand-receptor interactions and parasites can only invade immature RBCs (reticulocytes) expressing high levels of CD71, which account for up to 1.5% of circulating RBCs. CD71 is the receptor for PvRBP2b, a member of the P. vivax reticulocyte-binding protein (PvRBP) family. Another key pathway involves the Duffy-binding protein (PvDBP) and its receptor on RBCs, the Duffy antigen (DARC). RBCs lacking DARC are common among African descents and are refractory to P. vivax infection. The CD98 heavy chain (CD98hc) was recently identified as a reticulocyte-specific receptor for another PvRBP family member, PvRBP2a. Encoded by the SLC3A2 gene, CD98hc is part of a widely expressed multifunctional complex involved in amino acid transport, cell adhesion, immune activation, and murine erythropoiesis. We hypothesize that CD98hc might be a key modulator of human erythropoiesis and vivax malaria risk. Naturally occurring polymorphisms at the SLC3A2 locus that affect CD98hc expression or function might inhibit blood-stage P. vivax infection in two ways: (1) by accelerating human reticulocyte maturation, reducing CD71 expression and therefore inhibiting parasite entry via the CD71-PvRBP2b pathway and (2) by decreasing PvRBP2a binding affinity to its host-cell receptor, therefore partially blocking parasite entry via the alternative CD98hc-PvRBP2a pathway. This project aims at further exploring in vivo the dual role of CD98hc in human erythropoiesis and P. vivax infection. We will exploit unique humanized mice that support both human erythropoiesis and blood-stage P. vivax infection, with a focus on the bone marrow (the primary erythropoietic organ and extravascular reservoir of P. vivax). We will also characterize SLC3A2 polymorphism and anti-PvRBP2a antibody responses in a cohort of Amazonians with varying susceptibility to P. vivax infection. We will examine: (1) the role of CD98 in human erythropoiesis and P. vivax infection, (2) whether genetic diversity at the SLC3A2 locus and levels of anti-PvRBP2a antibodies in Amazonians are associated with their vivax malaria risk, and (3) the effects of CD98hc-targeted interventions in vivo on erythropoiesis and P. vivax infection. Our proposal is an international multidisciplinary effort that deploys several complementary expertise and resources, namely a unique in vivo humanized model of human erythropoiesis and P. vivax infection (French coordinator S. Garcia), field epidemiology and cohorts of P. vivax-exposed individuals in the Amazon (Brazilian coordinator M. U. Ferreira), genetics and invasion biology of malaria parasites (Brazilian Partner D. Y. Bargieri) and molecular immunology, malaria vaccines, and recombinant monoclonal antibody production (Brazilian Partner S. B. Boscardin). This project will generate new insights into P. vivax interactions with a key host-cell receptor, opening new opportunities to devise new therapeutics using anti-CD98hc strategies and anti-PvRBP2a-based vaccines.