Malaria Cell-Biology

Research Interests

Host-Parasite interactions that control the course of a malaria infection and the pathology associated with it. The laboratory focus on the study of mechanisms used by Plasmodium-induced host factors important for the maintenance of infection.

Group Members

Miguel Prudêncio	Postdoc
	Tel: 21 446 4516
Margarida Vigário	Postdoc
	Tel: 21 440 7900
Sílvia Portugal	External Ph.D. Student
	Tel: 21 446 4516
Fernanda Baptista	Trainee
	Tel: 21 446 4524
Ana Rita França	2003 PDIGC PhD Student
	Tel: 21 446 4527

Research Project

The role of host cell factors during the hepatic stages of a malaria infection

Plasmodium is the causative agent of malaria, one of the most prevalent and severe human infectious diseases. Anopheles mosquitoes inject sporozoites into the host, which rapidly migrate to the liver, invade hepatocytes and develop into merozoites that are released to the blood stream initiating repeated cycles of schizogony responsible for the disease symptoms. Because liver infection is the first obligatory step of the disease, hepatocyte-Plasmodium interactions that are crucial for the establishment of infection, constitute an ideal target for potential anti-malarial vaccines or preventive treatments. Parasites have developed a remarkable ability to survive in their hosts. It is becoming evident that intracellular parasites are masters at manipulating the host cell pathways for their own benefit, to create a more hospitable environment. Our aim is to identify hepatocyte genes that are differentially expressed at the transcript level as a result of Plasmodium development. Studies of pathogen-induced changes in host cells gene expression have relied on examination of the expression of a limited number of specific gene products. While these studies can be quite valuable ascertaining the role of known genes, the approach fails to provide information about genes for whom a functional role is not intuitive. The recent development of high-throughput methods for the analysis of gene expression under various conditions provides an opportunity to examine host-pathogen interaction, in an unbiased way. To achieve our aim, we will prepare cDNA probes from infected hepatocytes (at different times after infection) that will be hybridized to microarrays containing 15,000 mouse cDNAs. As a control for the baseline expression, we will use non-infected hepatocytes cDNA. This screen is expected to identify a large number of host cell genes whose transcript levels are significantly increased in response to a Plasmodium infection. Sporozoites traverse the cytosol of several hepatocytes before the final infection. During this migration, Plasmodium sporozoites disrupt the host plasma membranes. Our recent results show that host cell wounding by sporozoite migration induces the secretion of hepatocyte growth factor (HGF), which renders hepatocytes susceptible to infection. Infection depends on the activation of HGF receptor (MET). The malaria parasite exploits MET as a mediator of signals that make the host susceptible to infection. HGF is known to induce alterations on cell cytoskeleton, vesicular trafficking, lipid metabolism and apoptosis. We propose to determine the contribution of any of these effects on Plasmodium infection. We will also use mutated MET, which are able to separate the various signalling cascades.

Funding

POCTI/38563/MGI/2001
Host-Parasite Interactions during the Hepatic Stages of Malaria Infections.

Collaborators

NYU, USA
Ana Rodriguez

JHSPH, USA
George Dimopoulos

Research Project

The interactions of infected erythrocytes with host cells during malaria infections

Most morbidity and mortality from malaria is caused by infection with P. falciparum. Falciparum malaria is not simply a major public health problem but it is even considered to restrain economic growth in many parts of the world (7). The major reason for the lethality caused by this Plasmodium spp. is the fact that their infected erythrocytes express some adhesions able to mediate the adhesion of infected erythrocytes to host receptors on endothelium, uninfected erythrocytes, and platelets. In addition, it also know that during these stages infected erythrocytes also interact with other host cells such as dendritic cells and macrophages. Our aim is to study the role of there interactions during infections.

Funding

POCTI/MGI/44517/2002
Mechanism of action of HGF released by sporozoite-wounded hepatocytes during malaria infection.

Collaborators

IRCC, Italy
Silvia Giordano

NYU, USA
Ana Rodriguez

Publications

Carrolo, M., Giordano, S., Cabrita-Santos, L., Corso, S., Vigário, A.M., Silva, S., Leirião, P., Carapau, D., Armas-Portela, R., Comoglio, P., Rodriguez, A., and Mota, M.M. (2003). Hepaotcyte growth factor and its receptor are required for infection. Nature Medicine 9 :1363-1369

Mota, M.M., Rodriguez, A. (2002). Invasion of mammalian host cells by Plasmodium sporozoites. Bioessays 24(2) :149-56

Mota, M.M., Pradel, G., Vanderberg, J.P., Hafalla, J.C., Frevert, U., Nussenzweig, R.S., Nussenzweig, V., Rodriguez, A. (2001). Migration of Plasmodium sporozoites through cells before infection. Science 291 :(5501)141-4

Mota, M.M., Thathy, V., Nussenzweig, R.S., Nussenzweig, V. (2001). Gene targeting in the rodent malaria parasite Plasmodium yoelii. Mol Biochem Parasitol. 113(2) :271-8

Natarajan, R., Thathy, V., Mota, M.M., Hafalla, J.C., Menard, R., Vernick, K.D. (2001). Fluorescent Plasmodium berghei sporozoites and pre-erythrocytic stages: a new tool to study mosquito and mammalian host interactions with malaria parasites. Cell Microbiol. 3(6) :371-9

Mota, M.M., Rodriguez, A. (2001). Migration through host cells by apicomplexan parasites. Microbes Infect. 3(13) :1123-8

Mota, M.M., Jarra, W., Hirst, E., Patnaik, P.K., Holder, A.A. (2000). Plasmodium chabaudi-infected erythrocytes adhere to CD36 and bind to microvascular endothelial cells in an organ-specific way. Infect Immun. 68(7) :4135-44

Mota, M.M., Rodriguez, A. (2000). Plasmodium yoelii: efficient in vitro invasion and complete development of sporozoites in mouse hepatic cell lines. Exp Parasitol. 96(4) :257-9