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ROLE OF RED CELL MEMBRANE IN MALARIA PARASITE RELEASE

Award Number: R01AI050600
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: HEALTH SERVICES
PERIOD OF PERFORMANCE START DATE: 08/01/2002
PERIOD OF PERFORMANCE END DATE: 01/31/2007

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ROLE OF RED CELL MEMBRANE IN MALARIA PARASITE RELEASE - Plasmodium falciparum causes the most severe form of human malaria. During its 48-hour life cycle inside human red blood cells (RBCs) the parasite replicates into infective merozoites, which must then exit the host cell to invade new erythrocytes. Mounting evidence suggests that proteases are involved in host cell rupture and parasite release, although the molecular mechanisms underlying this process remain largely uncharacterized. Recently, we identified a novel P. falciparum cysteine protease named falcipain-2 (FP-2) that cleaves host erythrocyte membrane ankyrin, protein 4.1, adducin, and dematin with maximum proteolytic activity at late stages of parasite development. Based on our findings we propose that FP-2 mediates the cleavage of erythrocyte membrane skeletal proteins that are vital to the stability of red cell membrane, thus modulating the parasite release in vivo. The aim of this proposal is to define the functional role of FP-2 in vivo. Specifically, the following issues will be addressed: (1) What are the FP-2-mediated cleavage sites of erythrocyte ankyrin, adducin, and dematin? We have recently identified the site of protein 4.1 cleavage by FP-2, and have isolated an inhibitory peptide (Pi) that blocks all known functions of FP-2 in vitro. Similar strategy will be used to determine the precise sequence of the cleavage sites of ankyrin, adducin, and dematin. Also, we will determine the specificity of FP-2 by using a series of peptides derived from Pi in which critical residues are varied based on substrate specificities of other papain family enzymes. The potent peptide(s) will be selected to determine it's (their) effect on the intraerythrocytic growth and ultimate release of P. falciparum parasite. (2) Is parasite-derived cytosolic falcipain-2 accessible to the erythrocyte membrane skeleton in vivo? This will be achieved by immunodetection of FP-2 within parasite- infected erythrocytes, and in subcellular fractions, and by studying biosynthesis and maturation of FP-2. Furthermore, we will use a cell-permeable cysteine protease inhibitor in P. falciparum cultures as well as in the mouse in vivo model to elucidate the role of cysteine proteases in parasite release. (3) What is the role of falcipain-2 in th intraerythrocytic life cycle of P. falciparum? To directly confirm the function of FP-2 in vivo and to determine whether FP-2 alone is sufficient for parasite release, a model will be developed by disrupting the FP- 2 gene using gene targeting technology. Together, the proposed studies on FP-2 may begin to reveal molecular mechanisms underlying the release of malaria parasite from the host erythrocyte.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2006 ( Subtotal = $284,529 )
2006	2006	CARITAS ST ELIZABETH`S MEDICAL CENTER OF BOSTON	736 CAMBRIDGE ST, BOX OLH-6BD	BOSTON	MA	02135	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	5	2/7/2006	NON-COMPETING CONTINUATION	$284,529
														Subtotal = $284,529

Issue Date FY: 2005 ( Subtotal = $291,375 )
2005	2005	ST ELIZABETH'S HOSPITAL OF BOSTON	736 CAMBRIDGE ST, BOX OLH-6BD	BOSTON	MA	02135	SUFFOLK	USA	Microbiology and Infectious Diseases Research	000	4	2/11/2005	NON-COMPETING CONTINUATION	$291,375
														Subtotal = $291,375

Issue Date FY: 2004 ( Subtotal = $291,375 )
2004	2004	ST ELIZABETH'S HOSPITAL OF BOSTON	736 CAMBRIDGE ST, BOX OLH-6BD	BOSTON	MA	02135	SUFFOLK	USA	Microbiology and Infectious Diseases Research	000	3	1/19/2004	NON-COMPETING CONTINUATION	$291,375
														Subtotal = $291,375

Issue Date FY: 2003 ( Subtotal = $291,375 )
2003	2003	ST ELIZABETH'S HOSPITAL OF BOSTON	736 CAMBRIDGE ST, BOX OLH-6BD	BOSTON	MA	02135	SUFFOLK	USA	Microbiology and Infectious Diseases Research	000	2		NON-COMPETING CONTINUATION	$291,375
														Subtotal = $291,375

Issue Date FY: 2002 ( Subtotal = $145,688 )
2002	2002	ST ELIZABETH'S HOSPITAL OF BOSTON	736 CAMBRIDGE ST, BOX OLH-6BD	BOSTON	MA	02135	SUFFOLK	USA	Microbiology and Infectious Diseases Research	000	1	7/5/2002	NEW	$145,688
														Subtotal = $145,688

Grand Total All Awards = $1,304,342

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ROLE OF RED CELL MEMBRANE IN MALARIA PARASITE RELEASE

Award Number: R01AI050600

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: HEALTH SERVICES

PERIOD OF PERFORMANCE START DATE: 08/01/2002

PERIOD OF PERFORMANCE END DATE: 01/31/2007

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