Cheung Paul Kim-Ming, Yuan Ji, Zhang Huifang M, Chau David, Yanagawa Bobby, Suarez Agripina, McManus Bruce, Yang Decheng
Department of Pathology and Laboratory Medicine, University of British Columbia, The James Hogg iCapture Centre, St. Paul's Hospital, Vancouver, Canada.
J Med Virol. 2005 Nov;77(3):414-24. doi: 10.1002/jmv.20470.
Coxsackievirus B3 (CVB3) infects multiple organs of humans and causes different diseases such as myocarditis, pancreatitis, and meningitis. However, the mechanisms of organ-specific tropism are poorly understood. Coxsackievirus and adenovirus receptor (CAR) have been known to be important determinants for tissue tropism. However, current data on CAR mRNA expression in certain organs of mouse did not correlate well with the susceptibility of the respective tissues, suggesting that intracellular proteins may also play important roles in the regulation of viral infectivity through interaction with viral RNA. To search for such proteins and their interacting sites, we performed in situ hybridization to detect viral RNA in the organs of 4-week- and 10-week-old CVB3-infected mice and then correlated the data to patterns of host protein-viral RNA interactions. We found that heart and pancreas are the most heavily infected organs while the kidney remains highly resistant to the virus. The brain exhibited localized foci of viral replication, while the heart and liver showed random distribution of CVB3 RNA. The exocrine pancreas is highly susceptible to CVB3 infection but the endocrine cell type is resistant. In contrast to infections in other organs, mouse heart appears more resistant to CVB3 infection with increasing age. This resistance to infection in the kidney and older heart correlates well with the interaction of a 28 kDa mouse protein with the antisense sequence of nucleotides 210-529 of CVB3 5UTR. In addition, more intensified protein interactions were found within the nucleotides 530-630, a region that contains the internal ribosome entry site, which supports the previous findings that this segment plays critical roles in regulation of viral replication.
柯萨奇病毒B3（CVB3）可感染人体多个器官，并引发不同疾病，如心肌炎、胰腺炎和脑膜炎。然而，器官特异性嗜性的机制仍知之甚少。柯萨奇病毒和腺病毒受体（CAR）已被认为是组织嗜性的重要决定因素。然而，目前关于小鼠某些器官中CAR mRNA表达的数据与相应组织的易感性相关性不佳，这表明细胞内蛋白质也可能通过与病毒RNA相互作用在调节病毒感染性方面发挥重要作用。为了寻找此类蛋白质及其相互作用位点，我们进行了原位杂交，以检测4周龄和10周龄CVB3感染小鼠器官中的病毒RNA，然后将数据与宿主蛋白质-病毒RNA相互作用模式相关联。我们发现心脏和胰腺是感染最严重的器官，而肾脏对该病毒仍具有高度抗性。大脑呈现出病毒复制的局部病灶，而心脏和肝脏则显示CVB3 RNA随机分布。外分泌胰腺对CVB3感染高度敏感，但内分泌细胞类型具有抗性。与其他器官的感染情况不同，随着年龄增长，小鼠心脏对CVB3感染的抗性似乎更强。肾脏和老年心脏对感染的这种抗性与一种28 kDa小鼠蛋白与CVB3 5UTR核苷酸210 - 529反义序列的相互作用密切相关。此外，在核苷酸530 - 630区域发现了更强的蛋白质相互作用，该区域包含内部核糖体进入位点，这支持了先前的研究结果，即该片段在调节病毒复制中起关键作用。
