Professor

Infectologie
2705 boul. Laurier,
RC-9700 Sainte-Foy
(Quebec) CANADA G1V 4G2

Tel.: 418-654-4141, Ext. 7608
Fax: 418-654-2715
Email

Research Interests

Our main research program aims at identifying and characterizing the factors and the mechanisms involved in the pathogenesis of intracellular parasites. The model system we actually used is the protozoan parasite Leishmania. Pathogenic Leishmania species cause a diverse group of diseases, collectively called leishmaniasis, that range in severity from spontaneously healing skin ulcers to fatal visceral disease. Leishmania are intracellular parasites, which reside almost exclusively within mononuclear phagocytes of the mammalian host. There are two developmental forms of Leishmania, the motile promastigote transmitted to humans by the sand fly and the non-motile amastigote in the vertebrate host. The ability of Leishmania amastigotes to surviving in the adverse milieu of the phagolysosome and evading the defense mechanisms induced by the host is the key to the successful infection mounted by this pathogen. Genes preferentially expressed in response to various intracellular stimuli should play a central role in parasite's survival within the host cell. As part of the ongoing work in my laboratory, which is funded mainly by CIHR and Burroughs Wellcome Fund, we have initiated studies on the identification of genes specifically expressed in Leishmania's intracellular stage. Novel genes and mechanisms related to stage-specific expression were identified. Our main research interest is to assess the function of genes and/or proteins that are predominantly expressed upon macrophage infection and to delineate the molecular mechanisms, which control their stage-specific expression and contribute to parasite pathogenesis. We propose to use a global strategy based on a combination of genomics (DNA microarrays) and proteomics studies to isolate genes/proteins predominantly expressed upon contact or growth within the host cell. Our studies are focused on the L. donovani species that are responsible for the most severe form of the disease, the visceral leishmaniasis. The completion of the L. major genomic sequence (September 2003) and the recent initiative for sequencing the L. infantum genome should speed gene identification and allow, within the coming years, the development and use of several functional genomic-related technologies for analyzing the expression and the function of genes upon different intracellular conditions.

The specific objectives of my research program are to:

1. Identify genes/proteins of Leishmania donovani infantum that are specifically expressed upon parasite differentiation within the host macrophages
2. Investigate the mechanism(s) involved in the regulation of genes specifically expressed in the intracellular stage of the parasite
3. Study the function of genes important for parasite intracellular survival
4. Develop novel strategies for vaccination against intracellular pathogens

Possible outcomes of the ongoing research program

The identification of genes expressed predominantly upon growth of the parasites in the mammalian host and the study of the mechanism(s) that control their stage-specific regulation are fundamental for our understanding on how intracellular pathogens survive within their host and build an infection. With the progress anticipated in the field of functional genomics and microbe genomic sequencing, we should be in a position to globally address gene/protein expression and function in the L. donovani species, but also to initiate similar studies in other microbial pathogens. Overall, these studies should increase our understanding of the mechanisms controlling the pathogenesis of Leishmania parasites and should eventually lead to the identification of interesting targets for the development of effective vaccines and new drugs.

Selected References

Breton M, Zhao C, Ouellette M, Tremblay MJ, Papadopoulou B. (2007)

A recombinant non-pathogenic Leishmania vaccine expressing human immunodeficiency virus 1 (HIV-1) Gag elicits cell-mediated immunity in mice and decreases HIV-1 replication in human tonsillar tissue following exposure to HIV-1 infection. J Gen Virol. 88(Pt 1): 217-25.

Leprohon P, Legare D, Girard I, Papadopoulou B, Ouellette M. (2006)

Modulation of Leishmania ABC protein gene expression through life stages and among drug-resistant parasites. Eukaryot Cell. 5: 1713-25.

Dumas C, Chow C, Muller M, Papadopoulou B. (2006)

A novel class of developmentally regulated noncoding RNAs in Leishmania. Eukaryot Cell. 5: 2033-46.

Rafati S, Hassani N, Taslimi Y, Movassagh H, Rochette A, Papadopoulou B. (2006)

Amastin peptide-binding antibodies as biomarkers of active human visceral leishmaniasis. Clin Vaccine Immunol. 13: 1104-10.

Aude L. Foucher, Barbara Papadopoulou, Marc Ouellette (2006)

Prefractionation by digitonin extraction increases representation of the cytosolic and intracellular proteome of Leishmania infantum. Journal of Proteomic Research, 5: 1741-50.

François McNicoll, Jolyne Drummelsmith, Michaela Müller, Éric Madore, Nathalie Boilard, Marc Ouellette and Barbara Papadopoulou. (2006)

A combined proteomic and transcrptomic approach to the study of stage differentiation in Leishmania infantum. Proteomics, 6: 3567-81.

Zhao, C., Thibault, S., Messier, N., Ouellette, M., Papadopoulou, B., Tremblay, M.J. (2006)

"In primary human monocyte-derived macrophages exposed to HIV-1, does the increased intracellular growth of Leishmania infantum rely on its enhanced uptake?" J Gen Virol; 87 (5): 1295-1302.

Hafid Soualhine, Vicky Brochu, François Ménard, Barbara Papadopoulou, Karl Weiss, Michel G. Bergeron, Danielle Légaré, Jolyne Drummelsmith and Marc Ouellette (2005)

. A proteomic analysis of penicillin resistance in Streptococcus pneumoniae reveals a novel role for a phosphate ABC transporter. Molecular Microbiology. 58(5): 1430-1440.

François McNicoll, Michaela Müller, Serge Cloutier, Nathalie Boilard, Annie Rochette, Marthe Dubé, Barbara Papadopoulou. (2005)

Distinct 3’UTR elements regulate stage-specific mRNA accumulation and translation in Leishmania. Journal of Biological Chemistry. 280(42):35238-46.

Breton, M., Tremblay, M.J., Ouellette, M., and Papadopoulou, B. (2005)

A live non-pathogenic to humans parasitic vector as a vaccine candidate against visceral leishmaniasis. Infection and Immunity 73(10):6372-6382.

Rochette, A., McNicoll, F., Girard, J., Breton, M., Leblanc É., Bergeron MG, and Papadopoulou, B. (2005)

Characterization and developmental gene regulation of a large gene family encoding amastin surface proteins in Leishmania spp. Molecular and Biochemical Parasitology, 140:205-220.

Paul-André Genest, Bas ter Riet, Carole Dumas, Barbara Papadopoulou, Henri G.A.M van Luenen and Piet Borst. (2005)

Inactivation of the JBP1 locus results in the formation of linear amplicons. Nucleic Acids Research, 21;33(5):1699-1709.

Karima El Fadili, Nadine Messier, Philippe Leprohon, Gaétan Roy, Chantal Guimond, Nathalie Trudel, Nancy G. Saravia, Barbara Papadopoulou, Danielle Légaré and Marc Ouellette (2005)

Role of the ABC Transporter MRPA (PGPA) in Antimony Resistance in Leishmania infantum Axenic and Intracellular Amastigotes. Antimicrobial Agents of Chemotherapy, 49 (5): 1988-1993.

Zhao, C., Cantin, R., Breton, M., Papadopoulou, B., Tremblay, M.J. (2005)

DC-SIGN-mediated transmission of HIV-1 is compromised by the ability of Leishmania infantum to exploit also DC-SIGN as a ligand. Journal of Infectious Diseases. 191(10):1665-1669.

Marc Ouellette, Jolyne Drummelsmith and Barbara Papadopoulou (2004)

Leishmaniasis : Drugs in the clinic, resistance and new developments. Drug Resistance Updates. 7(4-5) :257-266.

Zhao, C., Papadopoulou, B., Tremblay, M.J. (2004)

"Leishmania infantum enhances human immunodeficiency virus type-1 replication in primary human macrophages through a complex cytokine network". Clinical Immunology. 113(1):81-88.

Boucher N., McNicoll F., Laverdière M., Rochette A., Chou, MN., Papadopoulou B. (2004)

The ribosomal RNA gene promoter and adjacent cis-acting DNA sequences govern plasmid DNA partitioning and stable inheritance in the parasitic protozoan Leishmania. Nucleic Acids Research, 25;32(9):2925-36.

Zhao, C., Papadopoulou, B., Tremblay, M.J. (2004)

"Leishmania infantum promotes replication of human immunodeficiency virus type 1 in human lymphoid tissue ex vivo by inducing secretion of the proinflammatory cytokines TNF-α and IL-1. Journal of Immunology, 172(5):3086-3093.

Dumas, C., Muyombwe, A., Roy, G., Matte, C., Ouellette, M., Olivier, M.and Papadopoulou, B. (2003)

Recombinant Leishmania major secreting biologically active Granulocyte Macrophage-Colony Stimulating Factor survive poorly in macrophages in vitro and produce delayed disease development in mice. Infection and Immunity, 71:6499-509.

Papadopoulou, B., Boucher, N., McNicoll, F., Wu, Y., Dubé, M. and Huang, X.F. (2003)

Amastigote-specific gene expression in Leishmania is controlled at the level of translation via a conserved 3'UTR element. Journal of Parasitology. In press.

Papadopoulou, B. , Huang, X.F., Boucher, N.,
McNicoll, F. (2003)

Stage-specific regulation of gene expression in Leishmania. Features, ASM News. 69(6) :282-288.

El Fakhry, Y., Ouellette, M. and Papadopoulou, B.(2002)

A proteomic approach to identify developmentally regulated proteins in Leishmania infantum. Proteomics, 2(8):1007-1017.

Boucher, N., Wu, Y., Dumas, C., Dubé, M., Sereno, D., Breton, M. and Papadopoulou, B.(2002)

A common mechanism of stage-regulated gene expression in Leishmania mediated by a conserved 3'UTR element J. Biol. Chem., 277(22):19511-19520.

Papadopoulou, B. , Roy, G., Breton, M., Kündig, C., Dumas, C., Fillion, I., Singh, A.K., Olivier, M. and Ouellette, M. (2002)

Reduced infectivity of a Leishmania donovani biopterin transporter BT1 genetic mutant and its use as an attenuated strain for vaccination. Infect. Immun., 70(1):62-68.

Boucher, N., McNicoll, F., Dumas, C. and
Papadopoulou, B. (2002)

RNA polymerase I-mediated transcription of a reporter gene integrated into different loci of Leishmania. Mol. Biochem. Parasitol., 119(1):153-158.

Publications - Barbara Papadopoulou