Isabelle Coppens, PhD
Center & Institute Affiliation(s):
PhD , University of Louvain , 1988
OBLIGATORY INTRACELLULAR PARASITISM: BIOLOGICAL ADAPTATIONS OF APICOMPLEXA INSIDE MAMMALIAN CELLS
Toxoplasma gondii, a leading opportunistic pathogen in immunosuppressive conditions, is an intracellular protozoan that must live in a membrane-bound compartment in mammalian cells in order to survive. By entering into the confines of a cell, Toxoplasma, like its cousin apicomplexan parasite Plasmodium that is responsible for malaria, assures itself a ready source of nutrients and protection from immune confrontations. This luxury crucially relies upon the successful entry into a target cell and avoidance of host cell defenses such as acidification or endo-lysosomal hydrolases. Unarguably, Apicomplexa are highly competent to establish a nonfusiogenic parasitophorous vacuole (PV) that provides a balance between the subversion of host defenses and the parasite's anabolic needs.
Our current interest is in studying the strategies used by T. gondii and Plasmodium to exploit host cell resources and disarm host cell defenses. Because of the abundance of organic molecules within mammalian cells, Apicomplexa have lost many genes required for the biosynthesis of vital components. In return, novel genes promoting host nutrient scavenging have become essential, and these genetic replacements are a successful scenario in order to achieve pathogenicity. By initially focusing on the dependency of Toxoplasma for host lipids, we discovered that this pathogen critically relies on cholesterol derived from plasma lipoproteins. Interference with low-density lipoprotein endocytosis or cholesterol translocation from lysosomes arrests parasite development. My group has next uncovered the mechanisms of cholesterol delivery from host endocytic compartments to the PV.
Unexpectedly, Toxoplasma can sequester nutrient-filled host lysosomes within invaginations of the PV membrane, which allows access to components supplied by the endocytic network. These observations have refuted the previous dogma asserting the complete seclusion of the PV from the host vesicular transport system and identify a unique mechanism for unidirectional transport of mammalian organelles. In the long term, we will decipher the microbial genes and pathways involved in the co-option of host cell processes and organelles by T. gondii.
These studies are extended to the malaria parasite, and more precisely to the stage infecting hepatocytes. Indeed, although the Plasmodium liver forms achieve one of the fastest growth rates among all organisms, nothing is known about Plasmodium-hepatocyte interactions. An exciting possibility is that the pathogenic mechanisms underlying the remarkable host-parasite interface might represent targets for the development of therapeutic strategies against Apicomplexa infections.
Of interest, the original features provided by the study of intracellular pathogenesis offer a unique perspective to elucidate basic questions in mammalian cell biology. Indeed as our understanding of the cell biology of Apicomplexa expands, novel and unexpected questions are presented, reaffirming the position of these parasites as a model system. In particular, our research might shed light on the routes of cholesterol trafficking, microtubule dynamics, membrane bilayer deformation and organelle degradation for other biological systems.
Honors and Awards
Faculty Innovation award from the Johns Hopkins University School of Public Health (2004) European Community Postdoctoral Research Award (1995) Prize from the French Rhône-Poulenc Rorer Foundation (1992) Prize of Pierre-J. & Edouard van Beneden from the Belgian Royal Academy of Sciences (1990) University of Louvain Research Award from the National Funds for Scientific Research (1989) University of Louvain Research Award from the National Funds for Scientific Research (1987) WHO Special Program for Research and Training in Tropical Disease Scholarship (1986) Institute for Scientific Research for Industry and Agriculture Encouragement Scholarship (1983)
- Plasmodium liver stage
- host cell-parasite interactions
- parasitophorous vacuole
- nutrient uptake
- cell biology
- drug targeting
-Jayabalasingham B, Voss C, Ehrenman K, Romano JD, Smith ME, Fidock DA, Bosch J and Coppens I. Characterization of the Atg8-conjugation system in two Plasmodium parasites with special focus on the liver stage: Possible linkage between the apicoplastic and autophagic systems? Autophagy, in press.
-Coppens I. Exploitation of auxotrophies and metabolic defects in Toxoplasma as therapeutic approaches. Int. J. Parasitol., in press.
-Coppens I (2013) Targeting lipid biosynthesis and salvage in apicomplexan parasites for improved chemotherapies. Nat. Rev. Microbiol. 11:823-835.
- Romano J, Sonda S, Bergbower E, Smith ME and Coppens I (2013) Toxoplasma gondii salvages sphingolipids from the host Golgi through the rerouting of selected Rab vesicles to the parasitophorous vacuole. Mol. Biol. Cell 24:1974-1995.
- Lige B, Sampels V and Coppens I (2013) Characterization of a second sterol-esterifying enzyme in Toxoplasma highlights the importance of cholesterol storage pathways for the parasite. Mol. Microbiol. 87:951-967.
- Ehrenman K, Wanyiri JW, Bhat N, Ward HD and Coppens I (2013) Cryptosporidium parvum scavenges LDL-derived cholesterol and micellar cholesterol internalized into enterocytes. Cell. Microbiol. 15:1182-1197.
- Romano JD, de Beaumont C, Carrasco JA, Ehrenman K, Bavoil PM and Coppens I (2013) Fierce competition between Toxoplasma and Chlamydia for host cell structures in dually infected cells. Eukaryot. Cell 12:265-277.
- Romano JD, de Beaumont C, Carrasco JA, Ehrenman K, Bavoil PM and Coppens I (2012) A novel co-infection model with Toxoplasma and Chlamydia trachomatis highlights the importance of host cell manipulation for nutrient scavenging. Cell. Microbiol. 15:619-646.
- Lige B, Romano JD, Bandaru VV, Ehrenman K, Levitskaya J, Sampels V, Haughey NJ and Coppens I (2011) Deficiency of a Niemann-Pick, type C1-related protein in Toxoplasma is associated with multiple lipidoses and increased pathogenicity. PLoS Pathog. 7:e1002410.
- Coppens I (2011) Metamorphoses of malaria: the role of autophagy in parasite diffferentiation. Essays Biochem. 51:127-136.
- Labaied M, Jayabalasingham B, Bano N, Cha SJ, Sandoval J, Guan G and Coppens I (2011) Plasmodium salvages cholesterol internalized by LDL and synthesized de novo in the liver. Cell. Microbiol. 13:569-586.
-Ehrenman K, Sehgal A, Lige B, Stedman TT, Joiner KA and Coppens I (2010) Novel roles for ATP-binding cassette G transporters in lipid redistribution in Toxoplasma. Mol. Microbiol. 76:1232-1249.
-Jayabalasingham B, Bano N and Coppens I (2010) Metamorphosis of the malaria parasite in the liver is associated with organelle clearance. Cell Res. 20:1043-1059.
-Lige B, Jayabalasingham B, Zhang H, Pypaert M and Coppens I (2009) Role of an ancestral D-bifunctional protein containing two sterol-carrier protein-2 domains in lipid uptake and trafficking in Toxoplasma. Mol. Biol. Cell. 20:658-672.
-Romano JD, Bano N and Coppens I (2008) New host nuclear functions are not required for the modifications of the parasitophorous vacuole of Toxoplasma. Cell. Microbiol. 10:465-476.
-Bano N, Romano JD, Jayabalasingham B and Coppens I (2007) Cellular interactions of Plasmodium liver stage with its host mammalian cell. Int. J. Parasitol. 37:1329-1341.
-Coppens I, Dunn JD, Romano JD, Pypaert M, Zhang H, Boothrod JC and Joiner KA (2006) Toxoplasma sequesters host lysosomes in the vacuolar space. Cell 125:261-274.
-Sehgal A, Bettiol S, Wenk MR, Pypaert M, Kaasch A, Blader I, Joiner KA and Coppens I (2005) Peculiarities of host cholesterol transport to the unique intracellular compartment containing Toxoplasma gondii. Traffic 6:1-17.
-Nishikawa N, Quittnat F, Stedman TT, Voelker DR, Choi JY, Zahn M, Yang M, Joiner KA and Coppens I (2005) Host cell lipids control cholesteryl ester synthesis and storage in intracellular Toxoplasma. Cell. Microbiol. 7:849-867.
-Quittnat F, Nishikawa Y, Stedman TT, Voelker DR, Choi JY, Zahn M, Murphy R, Martin W, Yang M, Joiner KA and Coppens I (2004) Synthesis of triacylglycerols in an ancient eukaryote: Identification and functional expression of a Toxoplasma DGAT1-related enzyme. Mol. Biochem. Parasitol. 138:107-122.
-Vielemeyer O, McIntosh MT, Joiner KA and Coppens I (2004) Neutral lipid synthesis and storage in the intraerythrocytic stages of Plasmodium falciparum. Mol. Biochem. Parasitol. 135:197-209.
-Coppens I and Joiner KA (2003) Host but not parasite cholesterol controls Toxoplasma cell entry by modulating organelle discharge. Mol. Biol. Cell 14:3804-3820.
-Coppens I, Sinai AP and Joiner KA (2000) Toxoplasma gondii exploits host low-density lipoprotein receptor-mediated endocytosis for cholesterol acquisition. J. Cell Biol. 149:167-180.