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J. Biol. Chem., Vol. 278, Issue 42, 40905-40910, October 17, 2003

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Molecular Mechanism of Host Specificity in Plasmodium falciparum Infection

ROLE OF CIRCUMSPOROZOITE PROTEIN^*,

Dharmendar Rathore  , Sybil C. L. Hrstka ¶, John B. Sacci, Jr. ||, Patricia De la Vega **, Robert J. Linhardt ¶, Sanjai Kumar  and Thomas F. McCutchan  

From the Growth and Development Section, Laboratory of Malaria and Vector Research, NIAID, National Institutes of Health, Bethesda, Maryland 20892, the Virginia Bioinformatics Institute, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, the ^¶Departments of Medicinal and Natural Products Chemistry, Chemistry, Chemical and Biochemical Engineering, University of Iowa, Iowa City, Iowa 52242, the ^||Department of Microbiology and Immunology, School of Medicine, University of Maryland, Baltimore, Maryland 21201, the ^**Malaria Program, Naval Medical Research Center, Silver Spring, Maryland 20910, and the Bacterial and Parasitic Diseases Section, Division of Emerging, Transfusion, and Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland 20852

Plasmodium falciparum sporozoites invade liver cells in humans and set the stage for malaria infection. Circumsporozoite protein (CSP), a predominant surface antigen on sporozoite surface, has been associated with the binding and invasion of liver cells by the sporozoites. Although CSP across the Plasmodium genus has homology and conserved structural organization, infection of a non-natural host by a species is rare. We investigated the role of CSP in providing the host specificity in P. falciparum infection. CSP from P. falciparum, P. gallinaceum, P. knowlesi, and P. yoelii species representing human, avian, simian, and rodent malaria species were recombinantly expressed, and the proteins were purified to homogeneity. The recombinant proteins were evaluated for their capacity to bind to human liver cell line HepG2 and to prevent P. falciparum sporozoites from invading these cells. The proteins showed significant differences in the binding and sporozoite invasion inhibition activity. Differences among proteins directly correlate with changes in the binding affinity to the sporozoite receptor on liver cells. P. knowlesi CSP (PkCSP) and P. yoelii CSP (PyCSP) had 4,790- and 17,800-fold lower affinity for heparin in comparison to P. falciparum CSP (PfCSP). We suggest that a difference in the binding affinity for the liver cell receptor is a mechanism involved in maintaining the host specificity by the malaria parasite.

Received for publication, June 13, 2003 , and in revised form, August 4, 2003.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Figs. S1 and S2.

To whom correspondence should be addressed: Laboratory of Malaria and Vector Research, NIAID, National Institutes of Health, Rm. 126, Bldg. 4, 4 Center Dr., MSC 0425, Bethesda, MD 20892-0425. Tel.: 301-496-6149; Fax: 301-402-0079; E-mail: tmccutchan{at}niaid.nih.gov.

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