: Malaria remains a major cause of death in humans worldwide. Despite the severity of this health problem, it is surprising that very little is known about the molecular mechanisms governing the invasion of Plasmodium into the liver at the subcellular level. Understanding sporozoite targeting to, entry into, and survival in the liver is of great importance to develop new approaches to fight the hepatic phase of malaria. Within minutes after transmission by an infected mosquito, malaria sporozoites are rapidly targeted to the liver and infect hepatocytes. To reach their initial site of multiplication in the mammalian host, the hepatocyte, sporozoites have to cross the continuous layer of sinusoidal cells. To accomplish this, sporozoites selectively recognize, invade, and pass through sinusoidal Kupffer cells, the stationary phagocytes of the liver. The broad long-term objective of this proposal is to understand the strategies mammalian Plasmodium species have developed to selectively recognize, actively invade, and safely passage through Kupffer cells, the professional stationary phagocytes of the liver, to reach their initial nurse cell in the host liver, the hepatocyte.
We aim to characterize the molecular recognition mechanism between malaria sporozoites and Kupffer cells, to define the composition of the compartment that harbors the parasites, and to determine the effect of the parasites on macrophage activation in a rodent model. We will also examine the interaction between P. gallinaceum, whose exoerythrocytic forms can differentiate and multiply inside phagocytic cells, and avian Kupffer cells. Finally, we wish to compare the data obtained from these animal models with the interaction between human Kupffer cells and P. falciparum sporozoites.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI051656-03
Application #
6730535
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Program Officer
Wali, Tonu M
Project Start
2002-09-30
Project End
2007-02-28
Budget Start
2004-03-01
Budget End
2005-02-28
Support Year
3
Fiscal Year
2004
Total Cost
$338,000
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
Frevert, Ute; Moreno, Alberto; Calvo-Calle, J Mauricio et al. (2009) Imaging effector functions of human cytotoxic CD4+ T cells specific for Plasmodium falciparum circumsporozoite protein. Int J Parasitol 39:119-32
Frevert, Ute; Spath, Gerald F; Yee, Herman (2008) Exoerythrocytic development of Plasmodium gallinaceum in the White Leghorn chicken. Int J Parasitol 38:655-72
Klotz, Christian; Frevert, Ute (2008) Plasmodium yoelii sporozoites modulate cytokine profile and induce apoptosis in murine Kupffer cells. Int J Parasitol 38:1639-50
Frevert, Ute; Nardin, Elizabeth (2008) Cellular effector mechanisms against Plasmodium liver stages. Cell Microbiol 10:1956-67
Baer, Kerstin; Klotz, Christian; Kappe, Stefan H I et al. (2007) Release of hepatic Plasmodium yoelii merozoites into the pulmonary microvasculature. PLoS Pathog 3:e171
Usynin, Ivan; Klotz, Christian; Frevert, Ute (2007) Malaria circumsporozoite protein inhibits the respiratory burst in Kupffer cells. Cell Microbiol 9:2610-28
Baer, Kerstin; Roosevelt, Michael; Clarkson Jr, Allen B et al. (2007) Kupffer cells are obligatory for Plasmodium yoelii sporozoite infection of the liver. Cell Microbiol 9:397-412
Tarun, Alice S; Baer, Kerstin; Dumpit, Ronald F et al. (2006) Quantitative isolation and in vivo imaging of malaria parasite liver stages. Int J Parasitol 36:1283-93
Korochkina, Svetlana; Barreau, Catherine; Pradel, Gabriele et al. (2006) A mosquito-specific protein family includes candidate receptors for malaria sporozoite invasion of salivary glands. Cell Microbiol 8:163-75
Frevert, Ute; Usynin, Ivan; Baer, Kerstin et al. (2006) Nomadic or sessile: can Kupffer cells function as portals for malaria sporozoites to the liver? Cell Microbiol 8:1537-46

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