VivaxEVTalk

Duration

01/09/2023 - 31/08/2026

Coordinator

Carmen Fernández & Hernando de Portillo

Funded by

Ministerio de Ciencia, Innovación y Universidades / Unión Europea / Agencia Estatal de Investigación (Ayuda PID2022-142908OB-I00)

Plasmodium vivax is considered a resilient parasite to malaria elimination as it has evolved cryptic asymptomatic infections representing up to 90% in endemic areas. Previously, we hypothesized that in addition to hypnozoites, P. vivax also evolved cryptic erythrocytic infections in the spleen and the bone marrow and that extracellular vesicles (EVs) from infections acted as intercellular communicators facilitating parasite sequestration in these organs. Moreover, that circulating EVs from asymptomatic carriers of hypnozoites contained specific parasite proteins; thus, identifying biomarkers of latent liver infection. Of relevance, we reported the first direct evidence of the physiological role of EVs in malaria (Toda et al., 2020. Nat Commun) and identify P. vivax proteins associated with EVs (Aparici-Herraiz et al., 2022. Front Cell Infect Microbiol). Moreover, global transcriptional analysis of parasite genes whose expression was dependent on an intact spleen, identified P. vivax spleen-dependent genes likely involved in cytoadherence (Fernández-Becerra et al., 2020. Proc Natl Acad Sci U S A). Furthermore, unequivocal evidence of the presence of the parasite in the spleen was obtained in a prospective collaborative study in Timika, Indonesia (Kho et al., 2021. N. Eng. J. Med). Noticeably, it was shown that asymptomatic individuals suffering traumatic spleen ruptures contained P. vivax parasites in their spleens representing the largest parasite biomass of asymptomatic chronic infections. In addition to the spleen, we reported morphological and RNAseq studies of bone marrow aspirates from seven patients revealing the presence of parasites in this tissue and identifying down-regulated human genes involved in erythropoiesis (Brito et al., 2022. J Infect Dis). Last, proteomics analysis of circulating EVs secreted from a humanized mouse model of P. vivax hypnozoites, identified potential EV biomarkers of latent liver infections (Gualdrón-López et al., 2022. Mol Cell Proteomics).

The overarching goal of this project is to further our innovative look at this new area of intercellular communication during cryptic erythrocytic infections in malaria by deciphering different levels of parasite-host interactions. Specifically, we will pursue our functional studies of already identified spleen and BM-dependent P. vivax genes through heterologous transfections; however, due to low efficiency of CRISPR/Cas9 transgene expression in P. falciparum observed in our previous project, we will implement the P. knowlesi system which is evolutionary more closely related to P. vivax. Moreover, we will use single-cell RNA approaches in our in vivo humanized mouse model of the bone marrow and the spleen to unveil cells, receptors and signaling pathways regulated by EVs from infections in these tissues. We will validate these data through qRT-PCR using samples of the human bone marrow and spleen from our model as well as from P. vivax patients from an endemic region. Last, we will perform studies of a human population in an endemic region of P. vivax to identify biomarkers of asymptomatic infections, as well as pursuing efforts to detect them using electrochemical biosensors.

This project, based on solid evidence and opening a new chapter on the biology and life cycle of P. vivax, will contribute breaking new grounds in the field of EVs, cell-cell communication, biomarker discovery as well as developing powerful methodologies for host-parasite studies.

Total Fuding

325.000,00 €