The Journal of Experimental Medicine
Keystone Symposia
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Published online 12 July 2004 doi:10.1084/jem.20032141
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 2, 169-179
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Role of Natural Killer Cells in Innate Protection against Lethal Ebola Virus Infection

Kelly L. Warfield1, Jeremy G. Perkins4, Dana L. Swenson1, Emily M. Deal1, Catharine M. Bosio2, M. Javad Aman2, Wayne M. Yokoyama5, Howard A. Young3, and Sina Bavari1

1 United States Army Medical Research Institute of Infectious Diseases, 2 Clinical Research Management, and 3 Laboratory of Experimental Immunology, National Cancer Institute, Frederick, Maryland 21702
4 Department of Hematology and Oncology, Walter Reed Army Medical Center, Washington DC 20307
5 Howard Hughes Medical Institute, Rhuematology Division, Washington University School of Medicine, St. Louis, MO 63110

Address correspondence to Sina Bavari, United States Army Medical Research Institute of Infectious Diseases, 1425 Porter St., Frederick, MD 21702. Phone: (301) 619-4246; Fax: (301) 619-2348; email: sina.bavari{at}amedd.army.mil

Ebola virus is a highly lethal human pathogen and is rapidly driving many wild primate populations toward extinction. Several lines of evidence suggest that innate, nonspecific host factors are potentially critical for survival after Ebola virus infection. Here, we show that nonreplicating Ebola virus-like particles (VLPs), containing the glycoprotein (GP) and matrix protein virus protein (VP)40, administered 1–3 d before Ebola virus infection rapidly induced protective immunity. VLP injection enhanced the numbers of natural killer (NK) cells in lymphoid tissues. In contrast to live Ebola virus, VLP treatment of NK cells enhanced cytokine secretion and cytolytic activity against NK-sensitive targets. Unlike wild-type mice, treatment of NK-deficient or -depleted mice with VLPs had no protective effect against Ebola virus infection and NK cells treated with VLPs protected against Ebola virus infection when adoptively transferred to naive mice. The mechanism of NK cell–mediated protection clearly depended on perforin, but not interferon-{gamma} secretion. Particles containing only VP40 were sufficient to induce NK cell responses and provide protection from infection in the absence of the viral GP. These findings revealed a decisive role for NK cells during lethal Ebola virus infection. This work should open new doors for better understanding of Ebola virus pathogenesis and direct the development of immunotherapeutics, which target the innate immune system, for treatment of Ebola virus infection.

Key Words: virus-like particles • filoviruses • immunity • matrix protein • glycoprotein

Abbreviations used in this paper: GP, glycoprotein; MCMV, murine cytomegalovirus; MIP, macrophage inflammatory protein; moi, multiplicity of infection; VLP, virus-like particle; VP, viral protein.


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