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Infection and Immunity, June 2000, p. 3667-3673, Vol. 68, No. 6
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Antibodies against Thrombospondin-Related Anonymous Protein Do Not Inhibit Plasmodium Sporozoite Infectivity In Vivo

Soren Gantt,1 Cathrine Persson,1 Keith Rose,2 Ashley J. Birkett,3 Ruben Abagyan,4,dagger and Victor Nussenzweig1,*

Department of Pathology1 and Skirball Institute,4 New York University School of Medicine, New York, New York 10016; Department of Medical Biochemistry, University Medical Centre, CH 1211 Geneva 4, Switzerland2; and Immune Complex Corporation, San Diego, California 921213

Received 16 December 1999/Returned for modification 24 January 2000/Accepted 9 February 2000

Thrombospondin-related anonymous protein (TRAP), a candidate malaria vaccine antigen, is required for Plasmodium sporozoite gliding motility and cell invasion. For the first time, the ability of antibodies against TRAP to inhibit sporozoite infectivity in vivo is evaluated in detail. TRAP contains an A-domain, a well-characterized adhesive motif found in integrins. We modeled here a three-dimensional structure of the TRAP A-domain of Plasmodium yoelii and located regions surrounding the MIDAS (metal ion-dependent adhesion site), the presumed business end of the domain. Mice were immunized with constructs containing these A-domain regions but were not protected from sporozoite challenge. Furthermore, monoclonal and rabbit polyclonal antibodies against the A-domain, the conserved N terminus, and the repeat region of TRAP had no effect on the gliding motility or sporozoite infectivity to mice. TRAP is located in micronemes, secretory organelles of apicomplexan parasites. Accordingly, the antibodies tested here stained cytoplasmic TRAP brightly by immunofluorescence. However, very little TRAP could be detected on the surface of sporozoites. In contrast, a dramatic relocalization of TRAP onto the parasite surface occurred when sporozoites were treated with calcium ionophore. This likely mimics the release of TRAP from micronemes when a sporozoite contacts its target cell in vivo. Contact with hepatoma cells in culture also appeared to induce the release of TRAP onto the surface of sporozoites. If large amounts of TRAP are released in close proximity to its cellular receptor(s), effective competitive inhibition by antibodies may be difficult to achieve.

* Corresponding author. Mailing address: NYU School of Medicine, Department of Pathology, Michael Heidelberger Division of Immunology, 550 First Ave., New York, NY 10016. Phone: (212) 263-5337. Fax: (212) 263-8179. E-mail: nussev01{at}popmail.med.nyu.edu.

dagger Present address: Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037.

Infection and Immunity, June 2000, p. 3667-3673, Vol. 68, No. 6
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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