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Journal of Virology, February 2007, p. 1923-1933, Vol. 81, No. 4
0022-538X/07/$08.00+0     doi:10.1128/JVI.02199-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Identification of Differentially Activated Cell-Signaling Networks Associated with Pichinde Virus Pathogenesis by Using Systems Kinomics ^,

Gavin C. Bowick,^1,2 Susan M. Fennewald,^1,2 Erin P. Scott,^1,2, LiHong Zhang,^1,2 Barry L. Elsom,^1,2 Judith F. Aronson,^1,2 Heidi M. Spratt,^3,4 Bruce A. Luxon,^2,3,4 David G. Gorenstein,^2,3 and Norbert K. Herzog^1,2*

Department of Pathology,¹ Center for Biodefense and Emerging Infectious Diseases,² Department of Biochemistry and Molecular Biology,³ Bioinformatics Program, University of Texas Medical Branch, Galveston, Texas 77555-0609⁴

Received 6 October 2006/ Accepted 16 November 2006

Phosphorylation plays a key role in regulating many signaling pathways. Although studies investigating the phosphorylated forms of signaling pathways are now commonplace, global analysis of protein phosphorylation and kinase activity has lagged behind genomics and proteomics. We have used a kinomics approach to study the effect of virus infection on host cell signaling in infected guinea pigs. Delineating the host responses which lead to clearance of a pathogen requires the use of a matched, comparative model system. We have used two passage variants of the arenavirus Pichinde, used as a biosafety level 2 model of Lassa fever virus as it produces similar pathologies in guinea pigs and humans, to compare the host cell responses between infections which lead to either a mild, self-limiting infection or lethal disease. Using this model, we can begin to understand the differences in signaling events which give rise to these markedly different outcomes. By contextualizing these data using pathway analysis, we have identified key differences in cellular signaling matrices. By comparing these differentially involved networks, we have identified a number of key signaling "nodes" which show differential phosphorylations between mild and lethal infections. We believe that these nodes provide potential targets for the development of antiviral therapies by acting at the level of the host response rather than by directly targeting viral proteins.

Published ahead of print on 6 December 2006.

Supplemental material for this article may be found at http://jvi.asm.org/.

Present address: Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104.

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