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Infection and Immunity, September 2005, p. 5883-5891, Vol. 73, No. 9
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.9.5883-5891.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Fetuin-A, a Hepatocyte-Specific Protein That Binds Plasmodium berghei Thrombospondin-Related Adhesive Protein: a Potential Role in Infectivity

Immunology and Infectious Diseases, Harvard School of Public Health, 665 Huntington Avenue, Boston, Massachusetts 02115-6018,¹ IZKF BIOMAT, University Hospital, Pauwelsstrasse 30, 52074, Aachen, Germany²

Received 3 November 2004/ Returned for modification 7 January 2005/ Accepted 19 May 2005

Malaria infection is initiated when the insect vector injects Plasmodium sporozoites into a susceptible vertebrate host. Sporozoites rapidly leave the circulatory system to invade hepatocytes, where further development generates the parasite form that invades and multiplies within erythrocytes. Previous experiments have shown that the thrombospondin-related adhesive protein (TRAP) plays an important role in sporozoite infectivity for hepatocytes. TRAP, a typical type-1 transmembrane protein, has a long extracellular region, which contains two adhesive domains, an A-domain and a thrombospondin repeat. We have generated recombinant proteins of the TRAP adhesive domains. These TRAP fragments show direct interaction with hepatocytes and inhibit sporozoite invasion in vitro. When the recombinant TRAP A-domain was used for immunoprecipitation against hepatocyte membrane fractions, it bound to 2-Heremans-Schmid glycoprotein/fetuin-A, a hepatocyte-specific protein associated with the extracellular matrix. When the soluble sporozoite protein fraction was immunoprecipitated on a fetuin-A-adsorbed protein A column, TRAP bound this ligand. Importantly, anti-fetuin-A antibodies inhibited invasion of hepatocytes by sporozoites. Further, onset of malaria infection was delayed in fetuin-A-deficient mice compared to that in wild-type C57BL/6 mice when they were challenged with Plasmodium berghei sporozoites. These data demonstrate that the extracellular region of TRAP interacts with fetuin-A on hepatocyte membranes and that this interaction enhances the parasite's ability to invade hepatocytes.

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Editor: J. F. Urban, Jr.