A. During the early stages of my scientific career, I worked in the field of metalloprotein biochemistry and enzymology, and on transient protein-protein interactions. During that period, my research focused on the characterization of several metal-containing proteins, particularly bacterial proteins bearing copper centers. I contributed to the elucidation of a hitherto unknown type of copper-containing active site, which had been a matter of debate for years prior to this report. Furthermore, I established a new technique to study protein-protein interactions using paramagnetic NMR spectroscopy. Overall, this work resulted in 16 publications in which I served as the primary or co-investigator.
B. Upon shifting my research focus to malaria, I became interested in gaining a better understanding of the liver-stage of an infection by Plasmodium, the malaria parasite. Over a period of several years, I made a number of important contributions to this field of study. Among others, I established new methods for the quantification of Plasmodium hepatic infection, employing transgenic parasites expressing fluorescent or luminescent proteins. Besides, I identified new host factors that play a role during infection of liver cells by Plasmodium, including a novel hepatocyte receptor termed SR-BI, and 5 kinases identified in a pioneering RNA interference screen aimed at the liver stage of infection by this parasite. Moreover, I contributed to the determination of the profile of the host cell transcriptome, showing that infected hepatoma cells undergo a coordinated sequence of events throughout malaria liver stage infection. I also studied ion homeostasis during the liver phase of the Plasmodium life cycle, having shown that the parasite induces changes in the activity of ion channels during infection. During this period, which marked my transition towards becoming a fully independent researcher, I published several primary research and review articles, most of which as primary investigator.
C. As I became increasingly independent, I kept an interest on the liver stage of Plasmodium infection but with a particular emphasis on its potential for anti-Plasmodial intervention. Thus, I carried out pioneering drug screens against Plasmodium liver stages and, in collaboration with various medicinal chemistry research laboratories, I contributed to the identification of novel compounds with anti-Plasmodial activity and to the development of novel hybrid molecules with dual-stage anti-malarial activity. Moreover, I investigated the development of immune responses against Plasmodium liver stages, showing that innate immunity against liver stage infection is activated by Plasmodium host cell sensors, and that malaria re-infection is inhibited by an innate immune response induced by plasmodium liver infection. Additionally, I revealed the crucial importance of Plasmodium Puf genes on parasite transmission to the mammalian host, and reported on the role of the Plasmodium rhomboid protease family on the parasite’s liver stage development.
D. As a fully independent scientist, I investigated the development of immune responses against Plasmodium liver stages, showing that innate immunity against liver stage infection is activated by Plasmodium host cell sensors, and that malaria re-infection is inhibited by an innate immune response induced by Plasmodium liver infection. I also demonstrated the crucial roles of GLUT1-mediated glucose uptake and CAT2-mediated arginine uptake and metabolism during hepatic infection by Plasmodium parasites, and I identified a novel interaction between Plasmodium EXP-1 and host ApoH proteins. More recently, I established a new method for in vitro sporozoite production and identification of transmission-blocking compounds and reported on the activity of antiretroviral compounds against Plasmodium liver stages. I currently lead several research projects, including a yet unpublished study funded by the Bill & Melinda Gates Foundation and the Malaria Vaccine Initiative towards the development of an innovative strategy for vaccination against malaria, and a study funded by iBET/Merck to establish a new 3D hepatic cell culture system for Plasmodium infection.
Complete List of Published Work (>70 publications):