Plasmodium vivax spleen-dependent genes encode antigens associated with cytoadhesion and clinical protection

Carmen Fernandez-Becerra (1, 2) , Maria Bernabeu (1) , Angélica Castellanos (3) , Bruna R Correa (4) , Thomas Obadia (5) , Miriam Ramirez (1) , Edmilson Rui (1) , Franziska Hentzschel (1) , Maria López-Montañés (1) , Alberto Ayllon-Hermida (1) , Lorena Martin-Jaular (1) , Aleix Elizalde-Torrent (1) , Peter Siba (6) , Ricardo Z Vêncio (4) , Myriam Arevalo-Herrera (3) , Socrates Herrera (3) , Pedro L Alonso (1) , Ivo Mueller (7, 5) , Hernando A del Portillo (1, 2, 8)

1 UB - Universitat de Barcelona
2 IGTP - Institut d’Investigació Germans Trias i Pujol = Germans Trias i Pujol Research Institute
3 Caucaseco scientific research center = Centro de Investigación Científica Caucaseco
4 USP - Universidade de São Paulo = University of São Paulo
5 Département Parasites et Insectes vecteurs - Department of Parasites and Insect Vectors
6 PNG-IMR - Papua New Guinea Institute of Medical Research
7 WEHI - The Walter and Eliza Hall Institute of Medical Research
8 ICREA - Institució Catalana de Recerca i Estudis Avançats = Catalan Institution for Research and Advanced Studies

Plasmodium vivax, the most widely distributed human malaria parasite, causes severe clinical syndromes despite low peripheral blood parasitemia. This conundrum is further complicated as cytoadherence in the microvasculature is still a matter of investigations. Previous reports in Plasmodium knowlesi, another parasite species shown to infect humans, demonstrated that variant genes involved in cytoadherence were dependent on the spleen for their expression. Hence, using a global transcriptional analysis of parasites obtained from spleen-intact and splenectomized monkeys, we identified 67 P. vivax genes whose expression was spleen dependent. To determine their role in cytoadherence, two Plasmodium falciparum transgenic lines expressing two variant proteins pertaining to VIR and Pv-FAM-D multigene families were used. Cytoadherence assays demonstrated specific binding to human spleen but not lung fibroblasts of the transgenic line expressing the VIR14 protein. To gain more insights, we expressed five P. vivax spleen-dependent genes as recombinant proteins, including members of three different multigene families (VIR, Pv-FAM-A, Pv-FAM-D), one membrane transporter (SECY), and one hypothetical protein (HYP1), and determined their immunogenicity and association with clinical protection in a prospective study of 383 children in Papua New Guinea. Results demonstrated that spleen-dependent antigens are immunogenic in natural infections and that antibodies to HYP1 are associated with clinical protection. These results suggest that the spleen plays a major role in expression of parasite proteins involved in cytoadherence and can reveal antigens associated with clinical protection, thus prompting a paradigm shift in P. vivax biology toward deeper studies of the spleen during infections.

Mots clés: Plasmodium vivax; cytoadherence; global transcription; spleen-dependent genes

Domaines: Microbiologie et Parasitologie

Carmen Fernandez-Becerra, Maria Bernabeu, Angélica Castellanos, Bruna R Correa, Thomas Obadia, et al.. Plasmodium vivax spleen-dependent genes encode antigens associated with cytoadhesion and clinical protection. Proceedings of the National Academy of Sciences of the United States of America, 2020, pp.201920596. ⟨10.1073/pnas.1920596117⟩. ⟨pasteur-02619599⟩