Miguel Prudêncio

Personal Statement

The combat against infectious diseases that exert a particularly heavy burden in the poorest regions of the globe constitutes not only a major scientific challenge but also a moral and social imperative. This is the main reason why, after my scientific career had been initiated in the field of protein biochemistry, it took a rather radical shift towards the study of malaria, the most prevalent parasitic disease in the developing world. My motivation for malaria research arises from a will to understand the complexity of the Plasmodium parasite, combined with a strong desire to contribute to its eradication. I am guided by the conviction that such an ambitious goal requires the combination of the knowledge driven by fundamental investigation with the specifically targeted approaches afforded by translational research. This is why, as a malaria researcher, I have not only sought to unveil novel aspects of the biology of Plasmodium infection, but also to identify novel antiplasmodial compounds and establish new experimental methodologies to study this parasite. One of my greatest ambitions, however, is to contribute to the development of a much-needed effective vaccine against this devastating disease. I have dedicated the greatest part of my research efforts as a Group Leader to this endeavor, through the pursuit of new knowledge on the immunology of Plasmodium liver infection, and the development of a completely novel approach to whole-sporozoite immunization against malaria. These efforts culminated in the generation and clinical validation of PbVac, the first member of this new class of candidates to vaccination against this disease. 

Contributions to Science

1. 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, and I established a completely novel technique to study protein-protein interactions using paramagnetic NMR spectroscopy.

• M. Prudêncio, A.S. Pereira, P. Tavares, S. Besson, I. Cabrito, K. Brown, B. Samyn, B. Devreese, J. Van Beeumen, F. Rusnak, G. Fauque, J. J. G. Moura, M. Tegoni, C. Cambillau and I. Moura (2000) “Purification, Characterization and Preliminary Crystallographic Study of Copper-Containing Nitrous Oxide Reductase from Pseudomonas nautica 617”, Biochemistry, 39, 3899-3907
• K. Brown, M. Tegoni, M. Prudêncio, A.S. Pereira, S. Besson, J. J. G. Moura, I. Moura and C. Cambillau (2000) “A Novel Type of Catalytic Copper Cluster in Nitrous Oxide Reductase”, Nature Struct. Biol., 7, 191-195
• M. Prudêncio, G. Sawers, S.A. Fairhurst, F.K. Yousafzai, R.R. Eady (2002) “Alcaligenes xylosoxidans Dissimilatory Nitrite Reductase: Alanine Substitution of the Surface-exposed Histidine 139 Ligand of the Type 1 Copper Center Prevents Electron Transfer to the Catalytic Center”, Biochemistry, 41, 3430-3438
• M. Prudêncio, J. Rohovec, J.A. Peters, E. Tocheva, M.J. Boulanger, M.E.P. Murphy, H.-J. Hupkes, W. Kosters, A. Impagliazzo, M. Ubbink (2004) “A Caged Lanthanide Complex as a Paramagnetic Shift Agent for Protein NMR”, Chem. Eur. J., 10, 3252-3260

2. 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. During this period, 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. I also 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. I also studied ion homeostasis during the liver phase of the Plasmodium life cycle, showing 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.

• M. Prudêncio, A. Rodriguez, M.M. Mota (2006), “The silent path to thousands of merozoites: the Plasmodium liver stage”, Nat. Rev. Microbiol., 4, 849-856
• M. Prudêncio, C.D. Rodrigues, R. Ataíde, M.M. Mota (2008), “Dissecting in vitro host cell infection by Plasmodium sporozoites using flow cytometry”, Cell. Microbiol., 10, 218-224
• M. Prudêncio, C.D. Rodrigues, M. Hannus, C. Martin, E. Real, L .A. Gonçalves, C. Carret, R. Dorkin, I. Röhl, K. Jahn-Hoffmann, A.J.F. Luty, R. Sauerwein, C.J. Echeverri, M.M. Mota (2008) “Kinome-Wide RNAi Screen Implicates at Least 5 Host Hepatocyte Kinases in Plasmodium Sporozoite Infection”, PloS Pathogens, 4, 1-15
• M. Prudêncio, E.T. Derbyshire, C.A. Marques, S. Krishna, M.M. Mota, H.M. Staines (2009) “Plasmodium berghei-infection induces volume-regulated anion channel-like activity in human hepatoma cells”, Cell. Microbiol., 11, 1492-1501

3. As an independent researcher, I have kept an interest on the liver stage of Plasmodium infection but with a particular focus on its potential for anti-malarial intervention. Thus, I unveiled new aspects of the biology of Plasmodium liver infection, demonstrating the crucial roles of GLUT1-mediated glucose uptake and CAT2-mediated arginine uptake and metabolism during this stage of infection by Plasmodium parasites, and I identified a novel interaction between Plasmodium EXP-1 and host ApoH proteins. Finally, I investigated co-infection by the sleeping sickness and malaria parasites, showing that an ongoing infection by the former inhibits hepatic infection by the latter and protects against malaria in mice.

• P. Meireles, J. Sales-Dias, C.M. Andrade, J. Mello-Vieira, L. Mancio-Silva, J.P. Simas, H.M. Staines, M. Prudêncio (2016) "GLUT1-mediated glucose uptake plays a crucial role during Plasmodium hepatic infection", Cell. Microbiol., doi:10.1111/cmi.12646
• C.S. Cunha, B. Nyboer, K. Heiss, M. Sanches-Vaz, D. Fontinha, E. Wiedtke, D. Grimm, J.M. Przyborski, M.M. Mota, M. Prudêncio*, A.K. Mueller* (2017) "P. berghei EXP-1 Interacts with Host Apolipoprotein H during Plasmodium Liver Stage Development", Proc. Natl. Acad. Sci. USA, 114, E1138-E1147
• P. Meireles, A.M. Mendes, R.I. Aroeira, B.C. Mounce, M. Vignuzzi, H.M. Staines, M. Prudêncio (2017) "Uptake and metabolism of arginine impact Plasmodium development in the liver", Sci. Rep., 7, DOI:10.1038/s41598-017-04424-y
• M. Sanches-Vaz, A. Temporão, R. Luis, H. Nunes-Cabaço, A.M. Mendes, S. Goellner, T. Carvalho, L.M. Figueiredo*, M. Prudêncio* (2019) "Trypanosoma brucei infection protects mice against malaria", PLoS Pathogens, 15, e1008145

4. Concomitantly, I carried out pioneering drug screens against Plasmodium liver stages and, in collaboration with various medicinal chemistry research laboratories, I contributed to the identification and development of novel compounds with anti-Plasmodial activity. I further established a new methodology aimed at the identification of Plasmodium transmission-blocking compounds, and established a novel platform for drug screening against Plasmodium hepatic infection.

• A.M. Mendes, I.S. Albuquerque, M. Machado, J. Pissarra, P. Meireles, M. Prudêncio (2017) "Inhibition of Plasmodium liver infection by ivermectin", Antimicrob. Agents and Chemother., 61, e02005-1613.
• R. Azevedo, M. Markovic, M. Machado, B. Franke-Fayard, A.M. Mendes, M. Prudêncio (2017) "A bioluminescence method for in vitro screening of Plasmodium transmission-blocking compounds", Antimicrob. Agents Chemother., 61, 202699-16
• M. Machado, M. Sanches-Vaz, J.P. Cruz, A.M. Mendes, M. Prudêncio (2017) "Inhibition of Plasmodium hepatic infection by antiretroviral compounds", Front. Cell. Infect. Microbiol., 7, DOI: 10.3389/fcimb.2017.00329
• F. Arez, S. Rebelo, D. Fontinha, D. Simão, T.R. Martins, M. Machado, C. Fischli, C. Oeuvray, L. Badolo, M. J. T. Carrondo, M. Rottmann, T. Spangenberg, C. Brito, B. Greco*, M. Prudêncio*, P.M. Alves* (2019) “Flexible 3D cell-based platforms for the discovery and profiling of novel drugs targeting Plasmodium hepatic infection”, ACS Infect. Dis., 5, 1831-1842
• D. Fontinha, F. Arez, I.R. Gal, G. Nogueira, D. Moita, T.H.H. Baeurle, C. Brito, T. Spangenberg, P.M. Alves, M. Prudêncio (2022) "Pre-erythrocytic activity of M5717 in monotherapy and combination in preclinical Plasmodium infection models", ACS Inf. Dis., 8, 721-727

5. As an independent scientist, I have further devoted a significant part of my efforts to understanding the immunology of Plasmodium liver infection, 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 hepatic infection. During this period, I also led the development of a novel approach to whole-sporozoite vaccination, based on the use of genetically modified P. berghei parasites as platforms for immunization against human malaria, having carried out the pre-clinical validation and clinical assessment of the first of this new class of candidates to vaccination.

• P. Liehl, V. Zuzarte-Luís, J. Chan, T. Zillinger, F. Baptista, D.l Carapau, M. Konert, K. Hanson, C. Carret, C. Lassnig, M. Müller, U. Kalinke, M. Saeed, A.F. Chora, D.T. Golenbock, B. Strobl, M. Prudêncio, L.P. Coelho, S.H. Kappe, G. Superti-Furga, A. Pichlmair, A.M. Vigário, C.M. Rice, K.A. Fitzgerald, W. Barchet, M.M. Mota (2014) "Host cell sensors for Plasmodium activate innate immunity against liver stage infection", Nature Med., 20, 47-53
• P. Liehl, P. Meireles, I.S. Albuquerque, M. Pinkevych, F. Baptista, M.M. Mota, M.P. Davenport, M. Prudêncio (2015), "Innate immunity induced by Plasmodium liver infection inhibits malaria reinfections", Infect. Immun., 83, 1172-1180
• A.M. Mendes, M. Machado, N. Gonçalves-Rosa, I.J. Reuling, L. Foquet, C. Marques, A.M. Salman, A.S.P. Yang, K.A. Moser, A. Dwivedi, C.C. Hermsen, B. Jiménez-Díaz, S. Viera, J.M. Santos, I. Albuquerque, S.N. Bhatia, J. Bial, I. Angulo-Barturen, J.C. Silva, G. Leroux-Roels, C.J. Janse, S.M. Khan, M.M. Mota, R.W. Sauerwein, M. Prudêncio (2018) "A Plasmodium berghei Sporozoite-Based Vaccination Platform Against Human Malaria", NPJ Vaccines, 3, 33
• A.M. Mendes, I.J. Reuling, C.M. Andrade, T.D. Otto, M. Machado, F. Teixeira, J. Pissarra, N. Gonçalves-Rosa, D. Bonaparte, J. Sinfrónio, M. Sanders, C.J. Janse, S.M. Khan, C.I. Newbold, M. Berriman, C. Lee, Y. Wu, C.F. Ockenhouse, R.W. Sauerwein, M. Prudêncio (2018) "Pre-Clinical Evaluation of a P. berghei-Based Whole-Sporozoite Malaria Vaccine Candidate", NPJ Vaccines, 3, 54
• I.J. Reuling, A.M. Mendes, G.M. de Jong GM, A. Fabra-García, H. Nunes-Cabaço, G.J. van Gemert, W. Graumans, L.E. Coffeng, S.J. de Vlas, A.S.P. Yang, C.K. Lee, Y. Wu, A.J. Birkett, C.F. Ockenhouse, R. Koelewijn, J.J. van Hellemond, P.J.J. van Genderen, R.W. Sauerwein, M. Prudêncio (2020) “Safety and efficacy of a genetically modified rodent malaria parasite against Plasmodium falciparum malaria: an open-label randomized phase 1/2a trial”, Science Transl. Med., 12, eaay2578

http://www.miguelprudencio.com/publications