Plasmodium vivax is one of the 5 species causing malaria in humans, and the leading cause of malaria outside Africa. A key step in P. vivax infection is the invasion of reticulocytes (young red blood cells) by the parasite. This invasion is made possible through several interactions between host receptors (reticulocyte membrane) and parasite ligands. While these interactions are well studied for P. falciparum, they remain elusive (and are not comparable) in P. vivax, due to the inability of long-term cultures. However, identifying parasite ligands and characterising the pathways used by the parasite to enter reticulocytes is essential for drug and vaccine development, and is the question that lies at the core of this project. In order to achieve P. vivax elimination, a better understanding of the ligands involved in invasion is necessary. We hypothesize that alternate pathways are used by P. vivax to invade reticulocytes, and that the PvTRAg and PvRBP multigenic families contain important invasion ligands. Therefore, we will carry out the first study integrating newly characterized P. vivax invasion phenotypes with transcriptomic and (epi-)genomic data in field isolates. As such, we expect to advance the knowledge on the role and regulation of PvTrag and PvRBP families in invasion and to discover new potential ligands. Candidate target ligands will be validated by ex vivo invasion assays, and will finally help us to identify the most suited drug and vaccine candidates.