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

Abstract

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, [LD 50 ], 10 3.0 PFU) but not in adult BALB/c mice at all of the doses tested (LD 50 , >10 5.0 PFU). Adult (BALB/c ؋ B6)F 1 mice were intermediately susceptible (LD 50 , 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.

Neuroinflammation resulting from covert brain invasion by common viruses – A potential role in local and global neurodegeneration

“…Dramatic mouse strain differences in susceptibility are seen in mouse hepatitis virus and Theiler's virus models [121,122]. Commonly employed mouse strains with very different immune responses, the BALB/c and C57BL/6 strains, respond very differently to disseminated viruses [123,124] and intranasal viruses [125]. In general, C57BL/6 mice are more resistant to viruses than BALB/c mice, but when they do succumb it is largely due to T cell-driven inflammation [124], not viral damage per se.…”

Viral Infections of Laboratory Mice

“…Disease is characterized by scruffiness, lethargy, stunted growth and often death within 10 days. Experimental infection of adult mice with MAdV-1 is most often subclinical and persistent but can cause fatal haemorrhagic encephalomyelitis with neurological symptoms, including tremors, seizures, ataxia and paralysis in susceptible C57BL/6 and DBA/2J mice [129]. BALB/c mice are relatively resistant to this condition.…”

“…Gross lesions in response to natural MAdV infections are not detectable. Occasional lesions observed after experimental infection with MAdV-1 include small surface haemorrhages in the brain and spinal cord of C57BL/6 and DBA/2J mice [129], duodenal haemorrhage in Foxn1 nu mice [130] and pale yellow livers in Prkdc scid mice [131].…”

“…Histologically, experimental MAdV-1 infection of suckling mice is characterized by multifocal necrosis and large basophilic intranuclear inclusion bodies in liver, adrenal gland, heart, kidney, salivary glands, spleen, brain, pancreas and brown fat [8,36,127,132]. In experimentally induced haemorrhagic encephalomyelitis, multifocal petechial haemorrhages occur throughout the brain and spinal cord, predominantly in the white matter, and are attributed to infection and damage to the vascular epithelium of the central nervous system (CNS) [129]. Histopathological manifestations in MAdV-1-infected Prkdc scid mice are marked by microvesicular fatty degeneration of hepatocytes [131].…”

Chemokines and viral diseases of the central nervous system

“…Mouse adenovirus-type 1 (MAV-1) is a double-stranded DNA virus that causes a fatal hemorrhagic encephalopathy in C57B1/6 mice within 4-6 days (Guida et al, 1995), along with infection of cerebrovascular endothelial cells. Chemokine gene expression was investigated and prominent induction of IP-10 was observed in the spleen and CNS of susceptible mice, whereas MCP-1 and MIP-2, respectively, were found in the spleen and brain of resistant mice (Charles et al, 1999).…”