Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA.
mBio. 2012 May 29;3(3). doi: 10.1128/mBio.00131-12. Print 2012.
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.
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.
对小鼠腺病毒 1 型（MAV-1）的易感性取决于小鼠品系；易感小鼠死于出血性脑脊髓炎。MAV-1 易感性数量性状基因座 Msq1 约占 BALB/c 和易感 SJL 小鼠之间感染 MAV-1 后（脑病毒载量）表型差异的 40%。使用区间特异性同基因小鼠品系（C.SJL-Msq1(SJL)），其中 SJL 衍生的等位基因 Msq1(SJL)存在于 BALB/c 背景中，我们证明 Msq1(SJL)控制着对 MAV-1 感染的高脑病毒滴度的发展，但不能解释 SJL 小鼠的总脑病理学或死亡率。C.SJL-Msq1(SJL) 小鼠在感染 MAV-1 后出现血脑屏障破坏和脑含水量增加，但这些影响分别较感染 SJL 小鼠的影响迟且不严重。如预期的那样，BALB/c 小鼠在这些检测中表现出最小的病理学。感染 SJL 和 C.SJL-Msq1(SJL)衍生的原代小鼠脑内皮细胞导致屏障特性丧失，而 BALB/c 衍生的细胞尽管同样能够支持 MAV-1 感染，但仍保持其屏障特性。最后，我们提供的证据表明，MAV-1 感染后器官病理学和炎性细胞向脑的募集均受 Msq1 影响。这些结果验证了 Msq1 是 MAV-1 感染的重要宿主因子，并细化了该基因座在 MAV-1 脑炎发展中的主要作用。它们进一步表明，在 MAV-1 感染的 SJL 小鼠中，发病机制涉及其他宿主因子或基因相互作用。
成功的病毒感染需要宿主和病毒因素；鉴定参与病毒复制和发病机制的宿主成分对于开发治疗干预措施很重要。先前已经确定了控制小鼠腺病毒 1 型（MAV-1）脑感染的遗传基因座（Msq1）。Msq1 中的基因属于与其他脑炎病毒（HIV-1 和西尼罗河病毒）易感性相关的基因家族。我们构建了一个区间特异性同基因小鼠品系，以研究 Msq1 对 MAV-1 易感性和脑发病率的贡献。我们比较了感染后的抗性、易感和同基因小鼠，以确定 Msq1 对 MAV-1 感染结果的影响程度，方法是比较已知的 MAV-1 脑疾病表现（存活、病毒载量、血脑屏障破坏、水肿、小鼠脑内皮细胞屏障特性、病理学和炎性细胞募集）。我们的结果表明，Msq1 是一个关键的宿主遗传因子，控制着 MAV-1 感染的许多方面。
