: In pregnant women, red blood cells infected with Plasmodium falciparum (IRBCs) selectively adhere in the pregnant women, placenta, causing several clinical manifestations including low birth weight, stillbirth, abortion of the fetus, and anemia and death in the mother. A number of studies have shown that the placental IRBC adherence is mediated by chondroitin 4-sulfate (C4S). During the previous grant period, it was established that a uniquely low sulfated chondroitin sulfate proteoglycan (CSPG) is the natural receptor for IRBC adherence in the placenta. Several critical structural elements of C4S involved in the process were determined. In contrast to the level of information available on the C4S structural interactions, very little is known about the parasite adhesive protein on the IRBC surface. Another aspect of the placental IRBC adherence that is not fully understood is the possible role of additional receptors. Recently, hyaluronic acid and fetal Fc receptor have been implicated, but their roles remain unclear. The long-term objective of this investigation is to delineate the structural interactions involved in the placental IRBC adherence, and use this knowledge to develop therapeutics and/or a vaccine for placental malaria. To accomplish this goal, the parasite adhesive protein has to be unequivocally identified and its adhesive domain determined. Therefore, the aims of this proposal are to investigate three important aspects that represent logical extensions of the studies during the previous granting period. (1) Determine fully the C4S structural elements involved in IRBC adhesion. Prepare photo-affinity probe using the structurally defined C4S dodecasaccharide. Isolate the parasite adhesive protein by photo-affinity tagging and by C4S-affinity chromatography and characterize biochemically. (2) Identify and characterize the parasite protein(s) by functional genomic approaches, and by C4S-IRBC adhesion inhibition analysis using antibodies against identified proteins. (3) Determine whether hyaluronic acid and fetal Fc receptor also mediate placental IRBC adhesion by testing blood samples from a large number of P. falciparum-infected placentas.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI045086-10
Application #
7166072
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Program Officer
Wali, Tonu M
Project Start
1999-05-01
Project End
2009-11-30
Budget Start
2007-01-01
Budget End
2007-12-31
Support Year
10
Fiscal Year
2007
Total Cost
$276,731
Indirect Cost
Name
Pennsylvania State University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
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Goel, Suchi; Gowda, D Channe (2011) How specific is Plasmodium falciparum adherence to chondroitin 4-sulfate? Trends Parasitol 27:375-81
Goel, Suchi; Valiyaveettil, Manojkumar; Achur, Rajeshwara N et al. (2010) Dual stage synthesis and crucial role of cytoadherence-linked asexual gene 9 in the surface expression of malaria parasite var proteins. Proc Natl Acad Sci U S A 107:16643-8
Singh, Kavita; Gitti, Rossitza K; Diouf, Ababacar et al. (2010) Subdomain 3 of Plasmodium falciparum VAR2CSA DBL3x is identified as a minimal chondroitin sulfate A-binding region. J Biol Chem 285:24855-62
Goyal, Atul; Goel, Suchi; Gowda, D Channe (2009) Plasmodium falciparum: Assessment of parasite-infected red blood cell binding to placental chondroitin proteoglycan and bovine tracheal chondroitin sulfate A. Exp Parasitol 123:105-10
Achur, Rajeshwara N; Kakizaki, Ikuko; Goel, Suchi et al. (2008) Structural interactions in chondroitin 4-sulfate mediated adherence of Plasmodium falciparum infected erythrocytes in human placenta during pregnancy-associated malaria. Biochemistry 47:12635-43
Achur, Rajeshwara N; Muthusamy, Arivalagan; Madhunapantula, SubbaRao V et al. (2008) Binding affinity of Plasmodium falciparum-infected erythrocytes from infected placentas and laboratory selected strains to chondroitin 4-sulfate. Mol Biochem Parasitol 159:79-84