Schraff Scott A, Brown David K, Schleiss Mark R, Meinzen-Derr Jareen, Greinwald John H, Choo Daniel I
Department of Pediatric Otolaryngology-Head and Neck Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA.
Otol Neurotol. 2007 Oct;28(7):964-9. doi: 10.1097/MAO.0b013e318067bd42.
The purpose of this study is to test the hypothesis that virally encoded immunomodulatory genes play a role in cytomegalovirus (CMV)-related hearing loss.
Cytomegalovirus is the leading cause of infectious-related congenital sensorineural hearing loss worldwide. Unfortunately, little is known about the pathophysiology of CMV-related injury to the developing ear.
Viral mutagenesis techniques were developed that allow the deletion of a specific viral immunomodulatory gene, macrophage inflammatory protein (MIP) 1alpha homolog. We assessed the extent to which this gene product contributed to auditory pathologic findings in the guinea pig (GP) model. Eighteen weanling GPs (250-350 g) were used under an Institutional Animal Control and Use Committee-approved protocol. We analyzed preinoculation hearing using auditory brainstem response recordings. Intracochlear inoculations were performed on one group of six GPs with sterile viral media, 6 GPs with wild-type (WT) CMV virus, and 6 GPs with mutant "knockout" (KO) virus (with deleted MIP-1alpha homolog). Auditory brainstem responses were then obtained on postinoculation Days 7, 14, 21, and 28.
There was a significant difference in hearing between the KO group and the WT group, with significantly better hearing in the KO group. A comparison of the KO group to the sham group revealed no significant hearing differences between the groups. The WT group had significant threshold shifts by dose at all frequencies meeting our criteria of hearing loss (>30 dB). There were no statistical differences in the sham or KO group.
Virally encoded immunomodulatory genes such as MIP-1alpha seem to play a significant role in CMV-related hearing loss. This study is the first demonstration of the role of specific viral immune modulation genes in the in vivo pathogenesis of CMV-induced hearing loss in a relevant animal model.
本研究的目的是检验病毒编码的免疫调节基因在巨细胞病毒（CMV）相关听力损失中起作用这一假说。
巨细胞病毒是全球感染相关先天性感音神经性听力损失的主要原因。遗憾的是，关于CMV对发育中耳朵造成损伤的病理生理学知之甚少。
开发了病毒诱变技术，可删除特定的病毒免疫调节基因，即巨噬细胞炎性蛋白（MIP）1α同源物。我们评估了该基因产物在豚鼠（GP）模型中对听觉病理结果的影响程度。在机构动物控制和使用委员会批准的方案下，使用了18只断奶的豚鼠（250 - 350克）。我们通过听觉脑干反应记录分析接种前的听力。对一组6只豚鼠进行耳蜗内接种无菌病毒培养基，6只豚鼠接种野生型（WT）CMV病毒，6只豚鼠接种突变的“敲除”（KO）病毒（缺失MIP - 1α同源物）。然后在接种后第7、14、21和28天获得听觉脑干反应。
KO组和WT组之间的听力存在显著差异，KO组听力明显更好。KO组与假手术组比较，两组之间听力无显著差异。WT组在所有符合我们听力损失标准（>30 dB）的频率下，阈值随剂量有显著变化。假手术组或KO组无统计学差异。
病毒编码的免疫调节基因如MIP - 1α似乎在CMV相关听力损失中起重要作用。本研究首次证明了特定病毒免疫调节基因在相关动物模型中CMV诱导的听力损失体内发病机制中的作用。
