Tabata Takako, Petitt Matthew, Fang-Hoover June, Zydek Martin, Pereira Lenore
Department of Cell and Tissue Biology, School of Dentistry, University of California, San Francisco, San Francisco, California.
Department of Cell and Tissue Biology, School of Dentistry, University of California, San Francisco, San Francisco, California.
Am J Pathol. 2016 Nov;186(11):2970-2986. doi: 10.1016/j.ajpath.2016.07.016. Epub 2016 Sep 13.
Human cytomegalovirus (HCMV) is the leading viral cause of birth defects, including microcephaly, neurological deficits, hearing impairment, and vision loss. We previously reported that epithelial cells in amniotic membranes of placentas from newborns with intrauterine growth restriction and underlying congenital HCMV infection contain viral proteins in cytoplasmic vesicles. Herein, we immunostained amniotic membranes from 51 placentas from symptomatic and asymptomatic congenital infection with HCMV DNA in amniotic fluid and/or newborn saliva, intrauterine growth restriction, preterm deliveries, and controls. We consistently observed HCMV proteins in amniotic epithelial cells (AmEpCs) from infected placentas, sometimes with aberrant morphology. Primary AmEpCs isolated from mid-gestation placentas infected with pathogenic VR1814 proliferated and released infectious progeny for weeks, producing higher virus titers than late-gestation cells that varied by donor. In contrast to intact virion assembly compartments in differentiated retinal pigment epithelial cells, infected AmEpCs made dispersed multivesicular bodies. Primary AmEpCs and explants of amniochorionic membranes from mid-gestation placentas formed foci of infection, and interferon-β production was prolonged. Infected AmEpCs up-regulated anti-apoptotic proteins survivin and Bcl-x by mechanisms dependent and independent of the activated STAT3. Amniotic membranes naturally expressed both survivin and Bcl-x, indicating that fetal membranes could foster persistent viral infection. Our results suggest strengthening innate immune responses and reducing viral functions could suppress HCMV infection in the fetal compartment.
人巨细胞病毒（HCMV）是导致出生缺陷的主要病毒原因，包括小头畸形、神经功能缺陷、听力障碍和视力丧失。我们之前报道过，患有宫内生长受限并伴有先天性HCMV感染的新生儿胎盘羊膜中的上皮细胞在细胞质囊泡中含有病毒蛋白。在此，我们对51份胎盘的羊膜进行了免疫染色，这些胎盘来自有症状和无症状的先天性HCMV感染，伴有羊水和/或新生儿唾液中的HCMV DNA、宫内生长受限、早产以及作为对照的情况。我们持续在受感染胎盘的羊膜上皮细胞（AmEpCs）中观察到HCMV蛋白，有时其形态异常。从中期妊娠胎盘分离出的原发性AmEpCs，感染致病性VR1814后可增殖并释放传染性子代病毒达数周之久，产生的病毒滴度高于晚期妊娠细胞，且不同供体的晚期妊娠细胞产生的病毒滴度有所差异。与分化的视网膜色素上皮细胞中完整的病毒体组装区室不同，受感染的AmEpCs形成了分散的多囊泡体。中期妊娠胎盘的原发性AmEpCs和羊膜绒毛膜外植体形成了感染灶，且干扰素-β的产生时间延长。受感染的AmEpCs通过依赖和不依赖于激活的STAT3的机制上调抗凋亡蛋白survivin和Bcl-x。羊膜天然表达survivin和Bcl-x，这表明胎膜可能促进病毒持续感染。我们的结果表明，增强先天免疫反应和降低病毒功能可能会抑制胎儿体内的HCMV感染。
