Division of Experimental Medicine, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California, USA.
J Virol. 2012 Dec;86(23):12795-805. doi: 10.1128/JVI.01054-12. Epub 2012 Sep 12.
Human cytomegalovirus (HCMV) is the leading viral cause of birth defects and life-threatening lung-associated diseases in premature infants and immunocompromised children. Although the fetal lung is a major target organ of the virus, HCMV lung pathogenesis has remained unexplored, possibly as a result of extreme host range restriction. To overcome this hurdle, we generated a SCID-hu lung mouse model that closely recapitulates the discrete stages of human lung development in utero. Human fetal lung tissue was implanted into severe combined immunodeficient (CB17-scid) mice and inoculated by direct injection with the VR1814 clinical isolate of HCMV. Virus replication in the fetal lung was assessed by the quantification of infectious virus titers and HCMV genome copies and the detection of HCMV proteins by immunohistochemistry and Western blotting. We show that HCMV efficiently replicated in the lung implants during a 2-week period, forming large viral lesions. The virus productively infected alveolar epithelial and mesenchymal cells, imitating congenital infection of the fetal lung. HCMV replication triggered apoptosis near and within the viral lesions and impaired the production of surfactant proteins in the alveolar epithelium. Our findings highlight that congenital and neonatal HCMV infection can adversely impact lung development, leading to pneumonia and acute lung injury. We have successfully developed a small-animal model that closely recapitulates fetal and neonatal lung development and provides a valuable, biologically relevant tool for an understanding of the lung pathogenesis of HCMV as well as other human respiratory viruses. Additionally, this model would greatly facilitate the development and testing of new antiviral therapies for HCMV along with select human pulmonary pathogens.
人类巨细胞病毒（HCMV）是导致早产儿和免疫功能低下儿童出生缺陷和危及生命的肺部疾病的主要病毒病原体。尽管胎儿肺是病毒的主要靶器官，但 HCMV 肺部发病机制仍未得到探索，这可能是由于宿主范围的极度限制。为了克服这一障碍，我们生成了一种 SCID-hu 肺小鼠模型，该模型很好地模拟了人类胎儿肺在子宫内的发育阶段。将人胎儿肺组织植入严重联合免疫缺陷（CB17-scid）小鼠中，并通过直接注射 HCMV 的 VR1814 临床分离株进行接种。通过定量传染性病毒滴度和 HCMV 基因组拷贝以及通过免疫组织化学和 Western blot 检测 HCMV 蛋白来评估胎儿肺中的病毒复制。我们表明，HCMV 在 2 周的时间内有效地在肺植入物中复制，形成大的病毒病变。该病毒有效地感染了肺泡上皮细胞和间充质细胞，模拟了胎儿肺的先天性感染。HCMV 复制在病毒病变附近和内部引发细胞凋亡，并损害肺泡上皮细胞中表面活性剂蛋白的产生。我们的研究结果表明，先天性和新生儿 HCMV 感染会对肺部发育产生不利影响，导致肺炎和急性肺损伤。我们已经成功开发了一种小动物模型，该模型很好地模拟了胎儿和新生儿肺的发育，并为理解 HCMV 以及其他人类呼吸道病毒的肺部发病机制提供了有价值的、生物学相关的工具。此外，该模型将极大地促进 HCMV 以及选定的人类肺部病原体的新型抗病毒疗法的开发和测试。
