Mouse adenovirus type 1 causes a fatal hemorrhagic encephalomyelitis in adult C57BL/6 but not BALB/c mice.

Mouse adenovirus type 1 (MAV-1) produces a lethal disease in newborn or suckling mice characterized by infectious virus and viral lesions in multiple organs. Previous reports of MAV-1 infection of adult mice generally described serologic evidence of infection without morbidity or mortality. However, our current results demonstrate that MAV-1 causes a fatal illness in adult C57BL/6(B6) mice (50% lethal dose, [LD50], 10(3.0) PFU) but not in adult BALB/c mice at all of the doses tested (LD50, > or = 10(5.0) PFU). Adult (BALB/c x B6)F1 mice were intermediately susceptible (LD50, 10(4.5) PFU). Clinically, the sensitive B6 mice showed symptoms of acute central nervous system (CNS) disease, including tremors, seizures, ataxia, and paralysis. Light microscopic examination of CNS tissue from the B6 animals revealed petechial hemorrhages, edema, neovascularization, and mild inflammation in the brain and spinal cord. Analysis by electron microscopy showed evidence of inflammation, such as activated microglia, as well as swollen astrocytic endfeet and perivascular lipid deposition indicative of blood-brain barrier dysfunction. Outside of the CNS, the only significant pathological findings were foci of cytolysis in the splenic white pulp. Assessment of viral replication from multiple tissues was performed by using RNase protection assays with an antisense MAV-1 early region 1a probe. The greatest amounts of viral mRNA in MAV-1-infected B6 animals were located in the brain and spinal cord. Less viral message was detected in the spleen, lungs, and heart. No viral mRNA was detected in BALB/c mouse tissue, with the exception of low levels in the heart. Viral titers of organ tissues were also determined and were concordant with RNase protection findings on the brain and spinal cord but failed to demonstrate significant infectious virus in additional organs. Our experiments demonstrate that MAV-1 has a striking tropism for the CNS that is strain dependent, and this provides an informative in vivo model for the study of adenoviral pathogenesis.

Mouse adenovirus type-1 replication is restricted to vascular endothelium in the CNS of susceptible strains of mice.

Previous studies have shown that mouse adenovirus type-1 (MAV-1) caused a fatal hemorrhagic encephalitis in certain strains of mice. C57BI/6 mice exhibited 100% mortality when given as little 10(3) plaque-forming units (PFU) of MAV, in contrast to BALB/c mice which were resistant to as many as 10(6) PFU. Susceptible animals died with a flaccid paralysis on the 3rd or 4th day after inoculation. The brains and spinal cords of these animals displayed numerous petechial hemorrhages that were found in virtually all areas of the brain, but were more numerous in white matter. In this paper, immunohistochemistry and electron microscopy were used to identify the viral target of replication within the CNS of susceptible mice. These studies showed that the CNS vascular endothelial cell was the primary site of viral replication within the CNS of mice infected with MAV-1. Characterization of cytokine mRNA levels and disease course in immunodeficient mice revealed that the host immune response played little, if any, role in the pathogenesis of MAV-1 disease in susceptible mice and was not responsible for the resistance of BALB/c mice. These results support the conclusion that disease course and outcome in susceptible and resistant strains of mice were determined primarily by the ability of the virus to replicate within the CNS vascular endothelium.