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Journal of Virology, April 2004, p. 3897-3905, Vol. 78, No. 8
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.8.3897-3905.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Membrane Cofactor Protein Is a Receptor for Adenoviruses Associated with Epidemic Keratoconjunctivitis{dagger}

Eugene Wu,1 Sunia A. Trauger,2 Lars Pache,1,3 Tina-Marie Mullen,1 Daniel J. Von Seggern,1 Gary Siuzdak,2 and Glen R. Nemerow1*

Departments of Immunology,1 Molecular Biology, The Scripps Research Institute, La Jolla, California 92037,2 Fachbereich Biologie, Chemie, Pharmazie, Freie Universität Berlin, 14195 Berlin, Germany3

Received 3 September 2003/ Accepted 15 December 2003

Subgroup D adenovirus (Ad) types 8, 19, and 37 (Ad8, -19, and -37, respectively) are causative agents of epidemic keratoconjunctivitis and genital tract infections. Previous studies showed that Ad37 binds to a 50-kDa membrane glycoprotein expressed on human ocular (conjunctival) cells. To identify and characterize the role of the 50-kDa glycoprotein in Ad37 infection, we partially purified this molecule from solubilized Chang C conjunctival cell membranes by using lentil lectin chromatography and preparative sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Liquid chromatography coupled to nano-electrospray ionization-tandem mass spectrometry was subsequently used to identify four Ad37 receptor candidates: CD46, CD87, CD98, and CD147. Immunodepletion analyses demonstrated that the 50-kDa protein is identical to CD46 (also known as membrane cofactor protein). The Ad37, but not Ad5, fiber knob bound to the extracellular domain of CD46, demonstrating a direct interaction of an Ad37 capsid protein with CD46. An antibody specific for the N-terminal 19 amino acids of CD46 also blocked Ad37 infection of human cervical carcinoma and conjunctival cells, indicating a requirement for CD46 in infection. Finally, expression of a 50-kDa isoform of human CD46 in a CD46-null cell line increased cell binding by wild-type Ad37 and gene delivery by an Ad vector pseudotyped with the Ad37 fiber, but not by a vector bearing the Ad5 fiber. Together, these studies demonstrate that CD46 serves as an attachment receptor for Ad37 and shed further light on the cell entry pathway of subgroup D Ads.

* Corresponding author. Mailing address: Department of Immunology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 784-9182. Fax: (858) 784-8472. E-mail: gnemerow{at}scripps.edu.

{dagger} This is manuscript no. 15965 from The Scripps Research Institute.

Journal of Virology, April 2004, p. 3897-3905, Vol. 78, No. 8
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.8.3897-3905.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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