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Journal of Virology, September 2009, p. 9398-9410, Vol. 83, No. 18
0022-538X/09/$08.00+0     doi:10.1128/JVI.00954-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Mouse Adenovirus Type 1-Induced Breakdown of the Blood-Brain Barrier{triangledown}

Lisa E. Gralinski,{dagger} Shanna L. Ashley, Shandee D. Dixon, and Katherine R. Spindler*

Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan 48109

Received 13 May 2009/ Accepted 24 June 2009

Infection with mouse adenovirus type 1 (MAV-1) results in fatal acute encephalomyelitis in susceptible mouse strains via infection of brain endothelial cells. Wild-type (wt) MAV-1 causes less brain inflammation than an early region 3 (E3) null virus in C57BL/6 mice. A mouse brain microvascular endothelial cell line infected with wt MAV-1 had higher expression of mRNAs for the proinflammatory chemokines CCL2 and CCL5 than mock- and E3 null virus-infected cells. Primary mouse brain endothelial cells infected with wt virus had elevated levels of CCL2 compared to mock- or E3 null virus-infected cells. Infection of C57BL/6 mice with wt MAV-1 or the E3 null virus caused a dose-dependent breakdown of the blood-brain barrier, primarily due to direct effects of virus infection rather than inflammation. The tight junction proteins claudin-5 and occludin showed reduced surface expression on primary mouse brain endothelial cells following infection with either wt MAV-1 or the E3 null virus. mRNAs and protein for claudin-5, occludin, and zona occludens 2 were also reduced in infected cells. MAV-1 infection caused a loss of transendothelial electrical resistance in primary mouse brain endothelial cells that was not dependent on E3 or on MAV-1-induced CCL2 expression. Taken together, these results demonstrate that MAV-1 infection caused breakdown of the blood-brain barrier accompanied by decreased surface expression of tight junction proteins. Furthermore, while the MAV-1-induced pathogenesis and inflammation were dependent on E3, MAV-1-induced breakdown of the blood-brain barrier and alteration of endothelial cell function were not dependent on E3 or CCL2.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, University of Michigan Medical School, 1150 W. Medical Center Dr., 6723 Medical Science Bldg. II, Ann Arbor, MI 48109-5620. Phone: (734) 615-2727. Fax: (734) 764-3562. E-mail: krspin{at}umich.edu

{triangledown} Published ahead of print on 1 July 2009.

{dagger} Present address: Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27599-7435.

Journal of Virology, September 2009, p. 9398-9410, Vol. 83, No. 18
0022-538X/09/$08.00+0     doi:10.1128/JVI.00954-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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