Giuseppe
Emeritus
[Source: PNAS, full text: (LINK). Abstract, edited.]
T-cell immunoglobulin and mucin domain 1 (TIM-1) is a receptor for Zaire Ebolavirus and Lake Victoria Marburgvirus
Edited* by Robert A. Lamb, Northwestern University, Evanston, IL, and approved April 7, 2011 (received for review December 21, 2010)
Abstract
The glycoproteins (GP) of enveloped viruses facilitate entry into the host cell by interacting with specific cellular receptors. Despite extensive study, a cellular receptor for the deadly filoviruses Ebolavirus and Marburgvirus has yet to be identified and characterized. Here, we show that T-cell Ig and mucin domain 1 (TIM-1) binds to the receptor binding domain of the Zaire Ebola virus (EBOV) glycoprotein, and ectopic TIM-1 expression in poorly permissive cells enhances EBOV infection by 10- to 30-fold. Conversely, reduction of cell-surface expression of TIM-1 by RNAi decreased infection of highly permissive Vero cells. TIM-1 expression within the human body is broader than previously appreciated, with expression on mucosal epithelia from the trachea, cornea, and conjunctiva?tissues believed to be important during in vivo transmission of filoviruses. Recognition that TIM-1 serves as a receptor for filoviruses on these mucosal epithelial surfaces provides a mechanistic understanding of routes of entry into the human body via inhalation of aerosol particles or hand-to-eye contact. ARD5, a monoclonal antibody against the IgV domain of TIM-1, blocked EBOV binding and infection, suggesting that antibodies or small molecules directed against this cellular receptor may provide effective filovirus antivirals.
Footnotes
- Andrew S. Kondratowicz (a), Nicholas J. Lennemann<SUP> </SUP>(b), Patrick L. Sinn (b)<SUP> </SUP>, Robert A. Davey<SUP> </SUP>(c), Catherine L. Hunt (a), Sven Moller-Tank (a), David K. Meyerholz (d), Paul Rennert (e), Robert F. Mullins (f), Melinda Brindley (a,1), Lindsay M. Sandersfeld (a), Kathrina Quinn (c), Melodie Weller (g), Paul B. McCray, Jr. (b), John Chiorini (g), and Wendy Maury (a,2)
Edited* by Robert A. Lamb, Northwestern University, Evanston, IL, and approved April 7, 2011 (received for review December 21, 2010)
Abstract
The glycoproteins (GP) of enveloped viruses facilitate entry into the host cell by interacting with specific cellular receptors. Despite extensive study, a cellular receptor for the deadly filoviruses Ebolavirus and Marburgvirus has yet to be identified and characterized. Here, we show that T-cell Ig and mucin domain 1 (TIM-1) binds to the receptor binding domain of the Zaire Ebola virus (EBOV) glycoprotein, and ectopic TIM-1 expression in poorly permissive cells enhances EBOV infection by 10- to 30-fold. Conversely, reduction of cell-surface expression of TIM-1 by RNAi decreased infection of highly permissive Vero cells. TIM-1 expression within the human body is broader than previously appreciated, with expression on mucosal epithelia from the trachea, cornea, and conjunctiva?tissues believed to be important during in vivo transmission of filoviruses. Recognition that TIM-1 serves as a receptor for filoviruses on these mucosal epithelial surfaces provides a mechanistic understanding of routes of entry into the human body via inhalation of aerosol particles or hand-to-eye contact. ARD5, a monoclonal antibody against the IgV domain of TIM-1, blocked EBOV binding and infection, suggesting that antibodies or small molecules directed against this cellular receptor may provide effective filovirus antivirals.
Footnotes
- <SUP>1</SUP>Present address: Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA 30322.
- <SUP>2</SUP>To whom correspondence should be addressed. E-mail: wendy-maury@uiowa.edu.
- Author contributions: A.S.K., N.J.L., P.L.S., R.A.D., D.K.M., P.B.M., J.C., and W.M. designed research; A.S.K., N.J.L., P.L.S., R.A.D., C.L.H., S.M.-T., D.K.M., M.B., L.M.S., K.Q., and W.M. performed research; P.R. and R.F.M. contributed new reagents/analytic tools; A.S.K., N.J.L., P.L.S., R.A.D., C.L.H., S.M.-T., D.K.M., R.F.M., L.M.S., K.Q., M.W., P.B.M., J.C., and W.M. analyzed data; and A.S.K., P.B.M., J.C., and W.M. wrote the paper.
- The authors declare no conflict of interest.
- *This Direct Submission article had a prearranged editor.
- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1019030108/-/DCSupplemental.