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
Complete
List of Published Work
(>130 publications):
http://www.miguelprudencio.com/publications