Exploring the dual role of CD98hc in human erythropoiesis and Vivax Malaria

• Grant number: 24/04280-2
• Support Opportunities: Research Projects - Thematic Grants
• Start date: January 01, 2025
• End date: December 31, 2028
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Agreement: ANR
• Principal Investigator: Marcelo Urbano Ferreira
• Grantee: Marcelo Urbano Ferreira
• Principal researcher abroad: Sylvie GARCIA
• Institution abroad: Institut Pasteur, France
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Pesquisadores principais: Silvia Beatriz Boscardin
• Associated researchers: Daniel Youssef Bargieri

Abstract

Plasmodium vivax causes 14.3 million infections annually, with 3.3 billion people at risk worldwide. No effective vaccine is available. P. vivax can only invade immature reticulocytes, expressing high levels of CD71, and <1.5% of circulating red blood cells (RBCs). CD71 is the receptor for PvRBP2b, a member of the P. vivax reticulocyte-binding protein (PvRBP) family. Another member, PvRBP2a has been recently recognized in vitro as the ligand for the reticulocyte CD98 heavy chain (CD98hc). Encoded by the SLC3A2 gene, CD98hc is part of a multifunctional complex involved in amino acid transport, cell adhesion, immune activation, and recently murine erythropoiesis. We hypothesize that CD98hc might be a key modulator of vivax malaria risk. In this context, changes in CD98hc expression or function due to naturally occurring polymorphism might reduce P. vivax infection (1) by accelerating RBC maturation and CD71 loss as observed in mice, thus inhibiting entry via the CD71-PvRBP2b pathway (2) by decreasing CD98hc binding affinity, thus inhibiting entry via the CD98hc-PvRBP2a pathway. Here, we will exploit our collaborative synergy to overcome existing roadblocks. To this end, we will use humanized mice model, that support both human erythropoiesis and blood-stage P. vivax infection (Partner 1), and P. vivax molecular epidemiology and a pre-existing cohort of Amazonians presenting varying susceptibility to P. vivax infection (Partner 2), to examine: (1) the role in vivo 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 human erythropoiesis and P. vivax infection. The insights into the recently unveiled P. vivax interaction with a key host-cell receptor should offer new opportunities for the design new anti-CD98hc-based therapeutics and PvRBP2a-based vaccines. (AU)