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Journal of Virology, January 2007, p. 332-348, Vol. 81, No. 1
0022-538X/07/$08.00+0     doi:10.1128/JVI.01592-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Cytomegalovirus InducesInterferon-Stimulated Gene Expression and Is Attenuated by Interferon in the Developing Brain{triangledown}

Anthony N. van den Pol,1* Michael D. Robek,2 Prabhat K. Ghosh,1 Koray Ozduman,1 Prasanthi Bandi,2 Matthew D. Whim,1,{dagger} and Guido Wollmann1

Departments of Neurosurgery,1 Pathology,Yale University School of Medicine, New Haven, Connecticut 065202

Received 25 July 2006/ Accepted 12 October 2006

Cytomegalovirus (CMV) is considered the most common infectious agent causing permanent neurological dysfunction in the developing brain. We have previously shown that CMV infects developing brain cells more easily than it infects mature brain cells and that this preference is independent of the host B- and T-cell responses. In the present study, we examined the innate antiviral defenses against mouse (m) and human (h) CMVs in developing and mature brain and brain cells. mCMV infection induced interferon (IFN)-stimulated gene expression by 10- to 100-fold in both glia- and neuron-enriched cultures. Treatment of primary brain cultures with IFN-{alpha}, -ß, and -{gamma} or a synthetic RNA, poly(I:C), reduced the number of mCMV-infected cells, both in older cells and in fresh cultures from embryonic mouse brains. When a viral dose that killed almost all unprotected cells was used, IFN-protected cells had a natural appearance, and when they were tested with whole-cell patch clamp recording, they appeared physiologically normal with typical resting membrane potentials and action potentials. mCMV infection increased expression of representative IFN-stimulated genes (IFIT3, OAS, LMP2, TGTP, and USP18) in both neonatal and adult brains to similarly large degrees. The robust upregulation of gene expression in the neonatal brain was associated with a much higher degree of viral replication at this stage of development. In contrast to the case for downstream gene induction, CMV upregulated IFN-{alpha}/ß expression to a greater degree in the adult brain than in the neonatal brain. Similar to the case with cultured brain cells, IFN treatment of the developing brain in vivo depressed mCMV replication. In parallel work with cultured primary human brain cells, IFN and poly(I:C) treatment reduced hCMV infection and prevented virus-mediated cell death. These results suggest that coupling IFN administration with current treatments may reduce CMV infections in the developing brain.

* Corresponding author. Mailing address: Department of Neurosurgery, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06520. Phone: (203) 785-5823. Fax: (203) 737-2159. E-mail: anthony.vandenpol{at}yale.edu.

{triangledown} Published ahead of print on 25 October 2006.

{dagger} Present address: Department of Biology, Pennsylvania State University, State College, PA 16802.

Journal of Virology, January 2007, p. 332-348, Vol. 81, No. 1
0022-538X/07/$08.00+0     doi:10.1128/JVI.01592-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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