Choukri Ben Mamoun PhD

Associate Professor of Medicine (Infectious Diseases) and of Microbial Pathogenesis

Research Interests

Malaria


Research Summary

Basic Research
Purine transport and metabolism in P. falciparum. P. falciparum cannot synthesize purine nucleotides de novo, and therefore the purine salvage pathway provides an indispensable nutritional function for the parasite and offers the prospect of selective therapeutic manipulation of malaria. The first step in purine acquisition by P. falciparum is the translocation of host purines into the parasite. P. falciparum has four putative purine transporter genes, PfNT1, PfNT2, PfNT3, and PfNT4. A major effort in the lab is to investigate the role of these transporters in parasite’s intraerythrocytic development and survival.

Membrane biogenesis in P. falciparum. During its 48-h asexual life cycle within human erythrocytes, P. falciparum grows to many times its own original size and divides to produce 16-32 new parasites. This rapid multiplication requires active synthesis of new membranes and is fueled by phospholipid precursors and fatty acids that are scavenged from plasma. A major focus of our research is to investigate the mechanism of membrane biogenesis and identification of enzymes that play an important role in Plasmodium growth, replication and sexual differentiation.

Therapy Program
Our therapy program builds upon the findings of our basic research program. There are two main topics investigated in this program: vaccine development and drug discovery.
Vaccine Development: Create transgenic parasites that can be used as attenuated malaria vaccines.
Drug development: Screen chemical libraries and design new compounds that target specific enzymes of the parasite.

Extensive Research Description

Malaria, caused by intraerythrocytic protozoan parasites of the genus Plasmodium, is by far the most pernicious and among the most prevalent of the parasitic diseases. Four species of Plasmodium (P. falciparum, P. malariae, P. ovale, and P. vivax) are known to be infectious to humans, and more recent cases of infection due to P. knowlesi have also been reported. These species cause approximately 300 - 500 million annual cases of clinical malaria resulting in 1.5 - 2.7 million deaths. Most fatalities can be ascribed to infection by P. falciparum.

Currently, there is no effective vaccine to combat malaria, and the current arsenal of medicines that have been used to treat and prophylax against P. falciparum infections is far from ideal. The need for new and more efficacious anti-malarial drugs and vaccines is acute. Plasmodium exhibits a complex life cycle consisting of a sexual phase within the Anopheles mosquito vector and an asexual phase with both exoerythrocytic and erythrocytic forms inside the human host. The ability to continuously propagate the erythrocytic form of P. falciparum in human red blood cells and the maturation of transfection technology that has provided a powerful vehicle for the genetic manipulation of the parasite genome makes this species of human malaria particularly suitable for the genetic, biochemical, and molecular biological investigations.


Selected Publications

  • Bobenchik AM, Witola WH, Augagneur Y, Nic Lochlainn L, Garg A, Pachikara N, Choi JY, Zhao YO, Usmani-Brown S, Lee A, Adjalley SH, Samanta S, Fidock DA, Voelker DR, Fikrig E, Ben Mamoun C. Plasmodium falciparum phosphoethanolamine methyltransferase is essential for malaria transmission. Proc Natl Acad Sci U S A. 2013 Nov 5;110(45):18262-7.
  • Augagneur Y, Jaubert L, Schiavoni M, Pachikara N, Garg A, Usmani-Brown S, Wesolowski D, Zeller S, Ghosal A, Cornillot E, Said HM, Kumar P, Altman S, Ben Mamoun C. Identification and functional analysis of the primary pantothenate transporter, PfPAT, of the human malaria parasite Plasmodium falciparum. J Biol Chem. 2013 Jul 12;288(28):20558-67.
  • Cornillot E, Dassouli A, Garg A, Pachikara N, Randazzo S, Depoix D, Carcy B, Delbecq S, Frutos R, Silva JC, Sutton R, Krause PJ, Mamoun CB. Whole genome mapping and re-organization of the nuclear and mitochondrial genomes of Babesia microti isolates. PLoS One. 2013 Sep 4;8(9):e72657.
  • Augagneur Y, Wesolowski D, Tae HS, Altman S, Ben Mamoun C. Gene selective mRNA cleavage inhibits the development of Plasmodium falciparum. Proc Natl Acad Sci U S A. 2012 Apr 17;109(16):6235-40.
  • Cornillot E, Hadj-Kaddour K, Dassouli A, Noel B, Ranwez V, Vacherie B, Augagneur Y, Brès V, Duclos A, Randazzo S, Carcy B, Debierre-Grockiego F, Delbecq S, Moubri-Ménage K, Shams-Eldin H, Usmani-Brown S, Bringaud F, Wincker P, Vivarès CP, Schwarz RT, Schetters TP, Krause PJ, Gorenflot A, Berry V, Barbe V, Ben Mamoun C. Sequencing of the smallest Apicomplexan genome from the human pathogen Babesia microti. Nucleic Acids Res. 2012 Oct;40(18):9102-14.
  • González-Bulnes P, Bobenchik AM, Augagneur Y, Cerdan R, Vial HJ, Llebaria A, Ben Mamoun C. PG12, a phospholipid analog with potent antimalarial activity, inhibits Plasmodium falciparum CTP:phosphocholine cytidylyltransferase activity. J Biol Chem. 2011 Aug 19;286(33):28940-7.
  • Downie MJ, El Bissati K, Bobenchik AM, Nic Lochlainn L, Amerik A, Zufferey R, Kirk K, Ben Mamoun C. PfNT2: a permease of the equilibrative nucleoside transporter family in the endoplasmic reticulum of Plasmodium falciparum. (2010) J. Biol. Chem285: 20827-33
  • April M. Bobenchik, Jae-Yeon Choi, Arunima Mishra, Iulian N. Rujan, Bing Hao, Dennis R. Voelker, Jeffrey C. Hoch and Choukri Ben Mamoun. Identification of inhibitors of Plasmodium falciparum phosphoethanolamine methyltransferase using an enzyme-coupled transmethylation assay. (2010) BMC Biochemistry, 11: 4
  • Ahmed S. Aly A, Megan, J. Downie, Choukri Ben Mamoun and Stefan H. Kappe. Subpatent infection with Nucleoside Transporter 1-deficient Plasmodium blood stage parasites confers sterile protection against lethal malaria in mice. (2010) Cell Microbiol. 12: 930-938.
  • Choukri Ben Mamoun, Sean T. Prigge and Henri Vial. Targeting the Lipid Metabolic Pathways for the Treatment of Malaria. (2010) Drug Development Research, 71: 44-55

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