Mouse adenovirus type 1-induced breakdown of the blood-brain barrier.
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.
Gralinski
Lisa E
LE
Department of Microbiology and Immunology, University of Michigan, Ann Arbor, 48109-5620, USA.
Ashley
Shanna L
SL
Dixon
Shandee D
SD
Spindler
Katherine R
KR
D000256:Adenoviridae / Q000472:pathogenicity*; D000257:Adenoviridae Infections / Q000473:pathology*; D000818:Animals; D001812:Blood-Brain Barrier / Q000821:virology*; D001921:Brain / Q000473:pathology / Q000821:virology; D018932:Chemokine CCL2 / Q000032:analysis; D017630:Connexins / Q000032:analysis; D015536:Down-Regulation; D042783:Endothelial Cells / Q000473:pathology / Q000821:virology; D017874:Immediate-Early Proteins / Q000172:deficiency; D007249:Inflammation; D008565:Membrane Proteins / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D019108:Tight Junctions / Q000821:virology
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D017630:Connexins; D017874:Immediate-Early Proteins; C484408:Laptm5 protein, mouse; D008565:Membrane Proteins