: Plasmodium sporozoites migrate through several cells in the host before infecting a final hepatocyte. Our Preliminary Studies show that this migration is essential for the establishment of malaria because; (i) it activates sporozoites making them competent for hepatocyte invasion; (ii) it activates neighboring hepatocytes making them susceptible for sporozoite infection. We plan to identify parasite and host cell mechanisms and molecules involved in these two crucial aspects of infection. (i) During migration through host cells sporozoites contact the cytosol of hepatocytes. This triggers exocytosis in sporozoites that is required for infection of hepatocytes. Using hepatocyte extracts we will identify the molecules that activate sporozoites for infection and the receptors that these molecules recognize in the sporozoite. We will also study the mechanism of signal transduction of this activation cascade resulting in exocytosis. (ii) Migration through host hepatocytes induces the release of hepatocyte growth factor (HGF) that makes hepatocytes susceptible for Plasmodium infection. We will investigate the mechanisms underlying HGF-mediated hepatocyte susceptibility for infection, including cytoskeletal rearrangements, acidification of the parasitophorous vacuole, cholesterol requirement, and hepatocyte apoptosis inhibition. Results from this study will contribute to the understanding of the molecular and cellular mechanisms mediating the first step of malaria development in the host: the infection of hepatocytes. The characterization of novel Plasmodium and hepatocyte factors that is required for infection hold significant potential as novel targets for disease control.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI053698-01A1
Application #
6678501
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Program Officer
Rogers, Martin J
Project Start
2003-08-01
Project End
2008-01-31
Budget Start
2003-08-01
Budget End
2004-01-31
Support Year
1
Fiscal Year
2003
Total Cost
$211,146
Indirect Cost
Name
New York University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
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Purcell, Lisa A; Leitao, Ricardo; Ono, Takeshi et al. (2010) A putative kinase-related protein (PKRP) from Plasmodium berghei mediates infection in the midgut and salivary glands of the mosquito. Int J Parasitol 40:979-88
Leitao, Ricardo; Rodriguez, Ana (2010) Inhibition of Plasmodium sporozoites infection by targeting the host cell. Exp Parasitol 126:273-7
Purcell, Lisa A; Wong, Kurt A; Yanow, Stephanie K et al. (2008) Chemically attenuated Plasmodium sporozoites induce specific immune responses, sterile immunity and cross-protection against heterologous challenge. Vaccine 26:4880-4
Ocana-Morgner, Carlos; Wong, Kurt A; Rodriguez, Ana (2008) Interactions between dendritic cells and CD4+ T cells during Plasmodium infection. Malar J 7:88
Wong, K A; Zhou, A; Rodriguez, A (2008) Protective immunity induced by daily bites from irradiated mosquitoes infected with Plasmodium yoelii. Parasite Immunol 30:482-6
Ono, Takeshi; Cabrita-Santos, Laura; Leitao, Ricardo et al. (2008) Adenylyl cyclase alpha and cAMP signaling mediate Plasmodium sporozoite apical regulated exocytosis and hepatocyte infection. PLoS Pathog 4:e1000008
Purcell, Lisa A; Yanow, Stephanie K; Lee, Moses et al. (2008) Chemical attenuation of Plasmodium berghei sporozoites induces sterile immunity in mice. Infect Immun 76:1193-9
Wong, Kurt A; Rodriguez, Ana (2008) Plasmodium infection and endotoxic shock induce the expansion of regulatory dendritic cells. J Immunol 180:716-26
Ono, Takeshi; Tadakuma, Takushi; Rodriguez, Ana (2007) Plasmodium yoelii yoelii 17XNL constitutively expressing GFP throughout the life cycle. Exp Parasitol 115:310-3

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