Plasmodium vivax Invasion Pathways into Human Reticulocytes – VIPeRs

P. vivax remains a major public health problem in developing countries. Like the other Plasmodium species, P. vivax has a complex life cycle involving multiple stages in the mosquito vector and human host. For instance, erythrocyte invasion is a complex process involving multiple interactions between Plasmodium merozoites and host erythrocytes. Unlike P. falciparum, which can use multiple erythrocyte receptors for invasion and has merozoite proteins with overlapping and redundant receptor-binding functions, invasion of human erythrocytes by P. vivax merozoites primarily relies on the interaction between the P. vivax Duffy Binding Protein (PvDBP) and the erythrocyte Duffy antigen receptor for chemokines (DARC). Consequently, PvDBP is considered a promising candidate for a P. vivax malaria vaccine. However, recently, a growing body of studies have reported PCR-positive vivax malaria cases in Duffy-negative individuals around the world, specifically across Africa and South America. These novel observations highlight the emerging issue of P. vivax infection in Duffy-negative populations, which questions the essential role of the PvDBP-DARC interaction and raises the possibility of alternative invasion mechanism(s), which have implications for the design of effective blood-stage vaccine candidates for P. vivax malaria

This application seeks to combine state-of-the-art genomic and biological approaches to characterize P. vivax invasion pathways involved in human Duffy-negative and Duffy-positive reticulocytes. We aim to identify P. vivax ligands involved in host cell invasion and understand how P. vivax has gained the capacity to infect reticulocytes from Duffy-negative individuals. Our strategy is based on a 2-step approach by taking full advantage of next-generation sequencing and functional biological analysis (including in vitro invasion asays and humanized mice infection assays) and by availing our access to P. vivax isolates from both Duffy-negative and Duffy-positive vivax malaria patients in Madagascar. Our strategy should overcome the main weakness of the previous investigations by exploring and characterizing the full repertoire of parasite ligands involved in invasion of human reticulocytes in Malagasy malaria endemic settings where two human populations with distinct Duffy blood group phenotypes (Duffy-negative and Duffy-positive) are frequently exposed to P. vivax.

The proposed work is timely and critical as this emerging capability of P. vivax circulating in Duffy-negative population is alarmingly reported and may add an additional hurdle to the control of vivax malaria. Understanding these host-parasite interactions is key to estimate the risk of emergence of vivax malaria in Africa and to develop novel intervention strategies such as vaccines against this pathogen. We are convinecd this work is likely to have a significant impact in our understanding of P. vivax infection. If successful, our findings will push the boundaries of our current understanding of host-pathogen interactions and host cell invasion by P. vivax merozoites. The results of the study will enable us to appraise the risk of emergence and spread of vivax malaria in Africa, which could be a real threat for public health for this population. Moreover, the availability of a P. vivax vaccine with high efficacy could greatly help malaria control and elimination efforts in large parts of the developing world.

This project brings together groups working on molecular biology (Didier Ménard) and parasite biology (Chetan Chitnis), along with malaria experts located in vivax malaria endemic area. The partners in this project thus bring complementary expertise and skills enabling a multi-disciplinary approach to a challenging problem.