How Plasmodium sporozoites invade hepatocytes, and develop within them, remains largely unknown. Our Preliminary Studies indicate that sporozoites can rapidly enter and leave host cells by disrupting the host cell plasma membrane. After few cycles of non-productive entry and exit, sporozoites invade host cells, and develop into the exo-erythrocytic stages. We propose that the passage of sporozoites through several cells is a required maturation step in the life cycle, and that it occurs during the parasite's journey from the site of entry in the skin to the liver. This hypothesis will be tested using cell and molecular biology approaches involving in vitro and in vivo models for hepatocyte infection. Our Preliminary Studies suggest that Plasmodium sporozoites ensure their complete development into the exo-erythrocytic stages by inhibiting apoptosis of hepatocytes. In contrast, irradiation of sporozoites prior to infection results in hepatocyte apoptosis. We propose to determine the genetic pathways involved in apoptosis inhibition of hepatocytes, and to identify the Plasmodium genes that contribute to this process, by examining gene expression in the host and pathogen in the presence and absence of irradiation. A protective immune response to malaria is induced by immunization with irradiated sporozoites. We propose that the apoptotic bodies derived from hepatocytes infected with irradiated sporozoites mediate the initiation of a protective anti-malaria immune response. Immunological and cell biological approaches will be used to further examine this hypothesis in vitro and in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049432-04
Application #
6690782
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Program Officer
Wali, Tonu M
Project Start
2001-02-01
Project End
2005-01-31
Budget Start
2004-02-01
Budget End
2005-01-31
Support Year
4
Fiscal Year
2004
Total Cost
$247,500
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
Leiriao, Patricia; Mota, Maria M; Rodriguez, Ana (2005) Apoptotic Plasmodium-infected hepatocytes provide antigens to liver dendritic cells. J Infect Dis 191:1576-81
Mota, Maria M; Rodriguez, Ana (2004) Migration through host cells: the first steps of Plasmodium sporozoites in the mammalian host. Cell Microbiol 6:1113-8
Carrolo, Margarida; Giordano, Silvia; Cabrita-Santos, Laura et al. (2003) Hepatocyte growth factor and its receptor are required for malaria infection. Nat Med 9:1363-9
Mota, Maria M; Hafalla, Julius C R; Rodriguez, Ana (2002) Migration through host cells activates Plasmodium sporozoites for infection. Nat Med 8:1318-22