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Updated: May 21, 2026
Dissecting Host-virus Interaction in Lytic Replication of a Model Herpesvirus
Published on: October 7, 2011
Contribution of a single host genetic locus to mouse adenovirus type 1 infection and encephalitis
Tien-Huei Hsu1, Irene W Althaus, Oded Foreman
1Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA.
Unlabelled:
Susceptibility to mouse adenovirus type 1 (MAV-1) is mouse strain dependent; susceptible mice die from hemorrhagic encephalomyelitis. The MAV-1 susceptibility quantitative trait locus Msq1 accounts for ~40% of the phenotypic (brain viral load) variance that occurs between resistant BALB/c and susceptible SJL mice after MAV-1 infection. Using an interval-specific congenic mouse strain (C.SJL-Msq1(SJL)), in which the SJL-derived allele Msq1(SJL) is present in a BALB/c background, we demonstrate that Msq1(SJL) controls the development of high brain viral titers in response to MAV-1 infection, yet does not account for the total extent of brain pathology or mortality in SJL mice. C.SJL-Msq1(SJL) mice had disruption of the blood-brain barrier and increased brain water content after MAV-1 infection, but these effects occurred later and were not as severe, respectively, as those noted in infected SJL mice. As expected, BALB/c mice showed minimal pathology in these assays. Infection of SJL- and C.SJL-Msq1(SJL)-derived primary mouse brain endothelial cells resulted in loss of barrier properties, whereas BALB/c-derived cells retained their barrier properties despite being equally capable of supporting MAV-1 infection. Finally, we provide evidence that organ pathology and inflammatory cell recruitment to the brain following MAV-1 infection were both influenced by Msq1. These results validate Msq1 as an important host factor in MAV-1 infection and refine the major role of the locus in development of MAV-1 encephalitis. They further suggest that additional host factors or gene interactions are involved in the mechanism of pathogenesis in MAV-1-infected SJL mice.
Importance:
A successful viral infection requires both host and viral factors; identification of host components involved in viral replication and pathogenesis is important for development of therapeutic interventions. A genetic locus (Msq1) controlling mouse adenovirus type 1 (MAV-1) brain infection was previously identified. Genes in Msq1 belong to the same family of genes associated with susceptibility to other encephalitic viruses, HIV-1 and West Nile virus. We constructed an interval-specific congenic mouse strain to examine the contribution of Msq1 to MAV-1 susceptibility and brain morbidity. We compared infected resistant, susceptible, and congenic mice regarding known MAV-1 disease manifestations in the brain (survival, viral loads, blood-brain barrier disruption, edema, mouse brain endothelial cell barrier properties, pathology, and inflammatory cell recruitment) to determine the extent to which Msq1 influences MAV-1 infection outcome. Our results showed that Msq1 is a critical host genetic factor that controls many aspects of MAV-1 infection.
Insights
A key genetic locus, Msq1, significantly influences susceptibility to mouse adenovirus type 1 (MAV-1) encephalitis by controlling viral load and blood-brain barrier integrity. However, additional host factors contribute to overall disease severity and mortality in infected mice.
Area of Science:
- Virology
- Immunology
- Genetics
Background:
- Mouse adenovirus type 1 (MAV-1) causes hemorrhagic encephalomyelitis, with susceptibility varying by mouse strain.
- A quantitative trait locus, Msq1, explains approximately 40% of the variance in brain viral load between resistant BALB/c and susceptible SJL mice.
- Genes within Msq1 are homologous to those implicated in susceptibility to other encephalitic viruses like HIV-1 and West Nile virus.
Purpose of the Study:
- To investigate the precise contribution of the Msq1 locus to MAV-1 susceptibility and brain pathology.
- To compare MAV-1 infection outcomes, including viral load, blood-brain barrier disruption, edema, and inflammatory responses, in resistant, susceptible, and congenic mouse strains.
- To elucidate the role of Msq1 in MAV-1-induced encephalitis and identify potential therapeutic targets.
Main Methods:
- Construction of an interval-specific congenic mouse strain (C.SJL-Msq1(SJL)) carrying the SJL-derived Msq1 allele on a BALB/c background.
- Comparative analysis of MAV-1 infection in BALB/c, SJL, and C.SJL-Msq1(SJL) mice, assessing survival, viral titers, blood-brain barrier integrity, brain edema, and histopathological changes.
- In vitro studies using primary mouse brain endothelial cells derived from different mouse strains to evaluate barrier properties and MAV-1 replication.
Main Results:
- The Msq1(SJL) allele in the congenic strain controlled high brain viral titers post-MAV-1 infection but did not fully account for the observed mortality or severe brain pathology in SJL mice.
- C.SJL-Msq1(SJL) mice exhibited delayed and less severe blood-brain barrier disruption and edema compared to SJL mice.
- Primary mouse brain endothelial cells from SJL and congenic mice showed compromised barrier function upon infection, while BALB/c cells maintained integrity despite supporting viral replication.
Conclusions:
- Msq1 is a critical host genetic factor significantly influencing MAV-1 brain viral load and contributing to blood-brain barrier dysfunction and encephalitis.
- While Msq1 plays a major role, additional host factors and gene interactions are involved in the pathogenesis of MAV-1 infection, particularly in SJL mice.
- Understanding the mechanisms controlled by Msq1 and other host factors is crucial for developing targeted interventions against MAV-1-induced neurological disease.
