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Journal of Virology, October 2006, p. 10109-10116, Vol. 80, No. 20
0022-538X/06/$08.00+0     doi:10.1128/JVI.01157-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Tyro3 Family-Mediated Cell Entry of Ebola and Marburg Viruses

Masayuki Shimojima,1,2 Ayato Takada,3 Hideki Ebihara,1,2,4 Gabriele Neumann,5 Kouki Fujioka,6 Tatsuro Irimura,6 Steven Jones,4,7 Heinz Feldmann,4,8 and Yoshihiro Kawaoka1,2,5,9*

Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639,1 Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012,2 Department of Global Epidemiology, Hokkaido University Research Center for Zoonosis Control, Sapporo 060-0818, Japan,3 Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba R3E 3R2, Canada,4 Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin—Madison, Madison, Wisconsin 53706,5 Laboratory of Cancer Biology and Molecular Immunology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033, Japan,6 Department of Immunology,7 Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba R3E 3R2, Canada,8 International Research Center for Infectious Diseases, Tokyo 108-8639, Japan9

Received 5 June 2006/ Accepted 31 July 2006

Filoviruses, represented by the genera Ebolavirus and Marburgvirus, cause a lethal hemorrhagic fever in humans and in nonhuman primates. Although filovirus can replicate in various tissues or cell types in these animals, the molecular mechanisms of its broad tropism remain poorly understood. Here we show the involvement of members of the Tyro3 receptor tyrosine kinase family—Axl, Dtk, and Mer—in cell entry of filoviruses. Ectopic expression of these family members in lymphoid cells, which otherwise are highly resistant to filovirus infection, enhanced infection by pseudotype viruses carrying filovirus glycoproteins on their envelopes. This enhancement was reduced by antibodies to Tyro3 family members, Gas6 ligand, or soluble ectodomains of the members. Live Ebola viruses infected both Axl- and Dtk-expressing cells more efficiently than control cells. Antibody to Axl inhibited infection of pseudotype viruses in a number of Axl-positive cell lines. These results implicate each Tyro3 family member as a cell entry factor in filovirus infection.

* Corresponding author. Mailing address: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Phone: 81-3-5449-5310. Fax: 81-3-5449-5408. E-mail: kawaoka{at}ims.u-tokyo.ac.jp.

Journal of Virology, October 2006, p. 10109-10116, Vol. 80, No. 20
0022-538X/06/$08.00+0     doi:10.1128/JVI.01157-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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