Ana Rodriguez, PhD, Assistant Professor

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Malaria is transmitted through the bite of an infected mosquito, which introduces Plasmodium sporozoites into the mammalian host. Sporozoites rapidly reach the liver of the host where they develop and replicate into merozoites, the parasitic stage that infects erythrocytes and causes the pathology of the disease. There is a significant lack of knowledge of the basic biological processes that mediate the survival of Plasmodium in its host. Our goal is to increase the understanding of these basic processes and use this knowledge to develop new strategies against the disease. We are currently investigating two different aspects of Plasmodium-host interactions:

The invasion of host hepatocytes by Plasmodium sporozoites

We found that Plasmodium sporozoites migrate through several hepatocytes before infecting a final one (Fig. 1) (Mota et al., 2000, Science 291: 141), this process induces regulated exocytosis in sporozoites activating them for hepatocyte invasion (Fig. 2) (Mota et al., 2002, Nature Medicine 8:1318). We have found that certain pyrimidine nucleotides and high concentrations of potassium, conditions that are found in the cytosol of cells while sporozoites migrate though them induce exocytosis and are required for infection. We intend to study the regulation of this process during malaria infections and identify the sporozoite receptor for these signals.

Fig. 1. Plasmodium sporozoites migrate through host cells inducing plasma membrane wounding, followed by repair. 105 P. yoelii sporozoites were added to monolayers of 2 x 105 Hepa1-6 cells (in 24-well plates) for 1 hour in the presence of 1 mg/ml FITC-dextran (green) to detect wounded cells. Cells were washed and incubated with 1 µg/ml propidium iodide (red) for 5 min before fixation to detect dead cells.

Fig. 2. Model for Plasmodium sporozoite migration in the liver: Migration of Plasmodium sporozoites through hepatocytes in the liver induces exocytosis that results in the exposure of transmembrane proteins, such as TRAP, in the surface of the sporozoite.

The interaction between Plasmodium infected erythocytes and the host innate immune system

Plasmodium infection induces immune suppression that is associated with the inability of infected individuals to prevent malaria re-infections throughout life, increased susceptibility to other infections and reduced response to vaccinations. We found that Plasmodium infected erythrocytes inhibit the activation of dendritic cells by inhibiting the up-regulation of co-stimulatory molecules, altering their cytokine secretion pattern and inhibiting their ability to activate T cells (Ocaña-Morgner et al., 2003. J. Exp. Med). Dendritic cells modulated by Plasmodium migrate to the spleen and secrete suppressive factors that inhibit the functions of T cells (Fig. 3). We found that Plasmodium-infected erythrocytes release a low molecular weight soluble factor that inhibits the activation of macrophages and dendritic cells. We intend to identify this factor and its receptor in host dendritic cells and macrophages and elucidate the signaling pathways mediating Plasmodium-induced immune suppression.

Fig.3. DCs in the T-cell areas of the spleen of malaria infected mice secrete the T-cell suppressive cytokines IL-10 and TGF-ß, but not the activatory cytokine IL-12. DCs loaded with (CFSE) (green) were i.v. injected in P. yoelii-infected or control mice. 24h later, spleens were removed and processed to obtain histological sections. Staining for T-cells with anti-CD3-phycoerythrin (red) shows the T-cell areas of the spleen. TGF-ß, IL-10 and IL-12 are stained in blue using specific antibodies coupled to biotin followed by incubation with avidin-marina-blue.

Selected Publications

1. Ocaña-Morgner C, Wong KA, Lega F, Dotor J, Borras-Cuesta F and A Rodriguez. Role of TGF-b and PGE2 in T cell responses during P. yoelii infection. European Journal of Immunology. 2007 Jun;37(6):1562-74.
2. Carapau D, Kruhofer M, Chatalbash A, Orengo JM, Mota MM and A Rodriguez. (2007). Transcriptome profile of dendritic cells during malaria: cAMP regulation of IL-6. Cellular Microbiology. 2007 Jul;9(7):1738-52. Epub 2007 Feb 23.
3. Takeshi Ono, Takushi Tadakuma and Ana Rodriguez. Plasmodium yoelii constitutively expressing GFP throughout the life cycle. Experimental Parasitology. Exp. Parasitol. 2007 Mar:115(3);310-13, e-pub Oct 2006.
4. J.C. Hafalla, U. Rai U, A. Morrot, D. Bernal-Rubio, F. Zavala and A. Rodriguez. Priming of CD8+ T cell responses following immunization with heat-killed Plasmodium sporozoites. European Journal of Immunology. 2006 May;36(5): 1179-86.
5. Leiriao P, Mota MM, Rodriguez A. Apoptotic Plasmodium-infected hepatocytes provide antigens to liver dendritic cells. J Infect Dis. 2005 May;191(10):1576-81.
6. Leiriao P, Albuquerque SS, Corso S, van Gemert GJ, Sauerwein RW, Rodriguez A., Giordano S, Mota MM. HGF/MET signalling protects Plasmodium-infected host cells from apoptosis. Cell Microbiol. 2005 Apr;7(4):603-9.
7. M. M. Mota and A. Rodriguez. Migration through host cells: the first steps of Plasmodium sporozoites in the mammalian host. Cellular Microbiology. 2004 Dec;6(12):1113-8.
8. M. Carrolo, S. Giordano, L. Cabrita-Santos, S. Corso, A. M. Vigario, S. Silva, P. Leiriao, D. Carapau, R. Armas-Portela, P. M. Comoglio, A. Rodriguez, and M. M. Mota. Hepatocyte growth factor and its receptor are required for malaria infection. Nature Medicine 2003;9, 1363 - 1369.
9. C. Ocaña-Morgner, M. M. Mota, and A. Rodríguez. Malaria blood-stage suppression of liver-stage immunity by dendritic cells. The Journal of Experimental Medicine 2003;197, 143-151. (#J46431)
10. M. M. Mota, J.C.R. Hafalla, and A. Rodriguez. Migration through host cells activates Plasmodium sporozoites for infection. Nature Medicine 2002;8, 1318-1322. (#J46433)
11. M. M. Mota, and A. Rodríguez. Invasion of mammalian host cells by Plasmodium sporozoites. BioEssays 2002;24, 149-156. (#J46434)
12. M. M. Mota, and A. Rodríguez. Migration through host cells by apicomplexan parasites. Microbes and Infection 2001;3, 1123-8. (#J25766)
13. O. Bruña-Romero, and A. Rodríguez. Dendritic cells can initiate protective immune responses against malaria. Infection and Immunity 2001;69, 5173-6. (#J23079)
14. M. M. Mota, and A. Rodríguez. Plasmodium invasion of mosquito cells: hawk or dove? Response from Mota and Rodriguez. Trends in Parasitology 2001;17, 212. (#J22629)
15. M. M. Mota, G. Pradel, U. Frevert, J. Vanderberg, J. Hafalla, R. Nussenzweig, V. Nussenzweig and A. Rodríguez. Migration of Plasmodium sporozoites through cells before infection. Science 2001;291, 141-144. (#J17776)
16. M. M. Mota, Giordano, L. and A. Rodriguez. Plasmodium sporozoite interactions with host cell: how important are the surroundings? Trends in Molecular Medicine. 2004; In Press.