Research project for a Master's or a PhD student in Virology and Immunology:
My main research interest is to understand the role of translational control in infectious diseases. During the infection process there is a constant interplay between the host and the pathogen that determines the outcome of the disease. In my laboratory, we investigate: (i) how the pathogen modulates the translation machinery of the host in order to survive, and (ii) how translational control influences the development of an efficient immune response to an infectious agent. Understanding how cell and, ultimately, patient immune responses are regulated will contribute to identify new potential points of therapeutic intervention.
Translational control (aka. regulation of protein synthesis) provides the cell with a rapid response to external triggers or cues. Thus, it constitutes an important regulatory step during infections. The molecular mechanisms involve: (i) the activation of the mTOR signaling pathway, (ii) the inhibition of the main translational repressor 4E-BP1 and (iii) the initiation of translation of immune-responsive transcripts. To counteract these effects, intracellular pathogens have evolved strategies to hijack/regulate the host translation initiation machinery and favor their own replication. These events have been mainly investigated in response to viruses; however, they remain largely unexplored during parasitic and bacterial infections. To address these questions, we have developed two main lines of research:
1) Translational control during Leishmania infection
We demonstrated for the first time that translational control is involved in the progression of a parasitic infection (cutaneous leishmaniasis) and that a protozoan parasite, Leishmania, can inhibit the translation initiation machinery of the macrophage, its host cell. We are currently identifying the mRNAs (e.g. microbicidal, pro-inflammatory), which are targeted in Leishmania-infected macrophages at the translational level. We also aim to identify the translation factors and the underlying intracellular signals involved in the immune response to Leishmania, using cellular and knock-out mouse models. Based on our work, regulators of translation might emerge as potential targets with therapeutic applications against leishmaniasis. Importantly, our findings raise the possibility that translational control also participates in infections caused by other protozoan parasites (e.g. Trypanosoma cruzi) and intracellular bacteria (e.g. Salmonella). To explore this possibility, we are currently developing collaborative projects with experts in various infectious models.
2) Molecular mechanisms of macrophage translational activation by Escherichia coli lipopolysaccharide
The Gram-negative bacterial endotoxin lipopolysaccharide (LPS) is one of the most potent inducers of inflammatory and antimicrobial responses in a number of immune cells, including macrophages. However, the implication of translational control in macrophage activation by LPS has been poorly studied. Our preliminary data indicate that LPS triggres a stronger inflammatory response in absence of the translational repressor 4E-BP1. We are currently investigating whether LPS regulates macrophage de novo protein synthesis and whether this occurs at the translation initiation step. Next, we will identify the mRNAs whose translation is enhanced by LPS and we will elucidate the molecular mechanisms involved. Altogether, our data will help to define the contribution of translational control (versus transcriptional regulation) to the inflammatory and antimicrobial effects mediated by LPS.
Herdy, B.*, M. Jaramillo*, Y.V. Svitkin, A. Rosenfeld, M. Kobayashi, D. Walsh, T. Alain, N. Robichaud, I. Topisirovic, L. Furic, R. J.O. Dowling, A. Sylvestre, L. Rong, R. Colina, M. Costa-Mattioli, J.H. Fritz, M. Olivier, E. Brown, I. Mohr and N. Sonenberg. 2012. Translational control of the activation of transcription factor NF-kappaB and production of type I interferon by phosphorylation of the translation factor eIF4E. Nature Immunology 13: 543-550.
*These authors equally contributed to this work.
Jaramillo, M., M.A. Gomez, O. Larsson, M.T. Shio, I. Topisirovic, I. Contreras, R. Luxenburg, A. Rosenfeld, R. Colina, R. McMaster, M. Olivier, M. Costa-Mattioli and N. Sonenberg. 2011. Leishmania Repression of Host Translation through mTOR Cleavage is Required for Parasite Survival and Infection. Cell Host & Microbe. 9: 331-41.
Jaramillo, M., M-J. Bellemare, C. Martel, A.P. Contreras, M. Godbout, M. Roger, E. Gaudreault, J. Gosselin, D.S. Bohle and M. Olivier. 2009. Synthetic Plasmodium-Like Hemozoin Activates the Immune Response per se: A Structure - Function Study. PLoS ONE 4:e6957.
Colina, R.*, M. Costa-Mattioli*, R.J.O. Dowling, M. Jaramillo, L. Tai, C.J. Breitbach, Y. Martineau, O. Larsson, L. Rong, Y.V. Svitkin, A.P. Makrigiannis, J.C. Bell and N. Sonenberg. 2008. Translational control of the innate immune response through IRF-7. Nature 452:323-328.
*These authors contributed equally to this work.
Jaramillo, M., M. Godbout, and M. Olivier. 2005. Hemozoin induces macrophage chemokine expression through oxidative stress-dependent and -independent mechanisms. The Journal of Immunology 174:475-84.
Jaramillo, M., P.H. Naccache, and M. Olivier. 2004. Signaling events involved in macrophage chemokine expression in response to monosodium urate crystals. The Journal of Biological Chemistry 279:52797-805.
Jaramillo, M., P.H. Naccache, and M. Olivier. 2004. Monosodium urate crystals synergize with IFN-gamma to generate macrophage nitric oxide: Involvement of ERK1/2 MAPK and NF-kappaB. The Journal of Immunology 172:5734-42.
Jaramillo, M., I. Plante, N. Ouellette, K. Vandal, P.A. Tessier, and M. Olivier. 2004. Hemozoin-inducible proinflammatory events in vivo: Potential role in malaria infection. The Journal of Immunology 172: 3101-10.
Jaramillo, M., D.C. Gowda, D. Radzioch, and M. Olivier. 2003. Hemozoin increases IFN-gamma-inducible macrophage nitric oxide generation through ERK- and NF-kappaB-dependent pathways. The Journal of Immunology 171:4243-53.
Blanchette, J., M. Jaramillo, and M.Olivier. 2003. Signaling events involved in IFN-gamma-inducible macrophage nitric oxide generation. Immunology 108:513-22.
Jaramillo, M., and M. Olivier. 2002. Hydrogen peroxide induces murine macrophage chemokine gene transcription via ERK- and cAMP-dependent pathways: Involvement of NF-kappaB, AP-1 and CREB. The Journal of Immunology 169:7026-38.
Winograd, E., C. Clavijo, L. Bustamante, and M. Jaramillo. 1999. Release of merozoites from Plasmodium falciparum-infected erythrocytes could be mediated by a non-explosive event. Parasitology Research 85:621-24.
Jaramillo, M. 2009. Malaria Immunopathology: Signaling and Cellular Mechanisms Involved in Hemozoin-inducible Proinflammatory Events. Saarbrücken, Germany. VDM Verlag Dr. Müller Aktiengesellschaft & Co. KG. pp.159.
Olivier, M., and M. Jaramillo. 2007. Modulation of Positive Signaling and Proinflammatory Responses by Hemozoin, a Plasmodium Metabolic Waste. In Protozoans in Macrophages. E.Y. Denkers and R.T. Gazzinelli, eds. Austin, Texas U. S. A. Landes Bioscience, pp. 67 - 83.