Animal Reproduction and Biotechnology Laboratory, Department of Biomedical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, 1683 Campus Delivery, Fort Collins, CO 80523-1683, USA.
Virus Res. 2012 Aug;167(2):329-36. doi: 10.1016/j.virusres.2012.05.018. Epub 2012 May 30.
Transplacental viral infections are dependent upon complex interactions between feto-placental and maternal immune responses and the stage of fetal development at which the infection occurs. Bovine viral diarrhea virus (BVDV) has the ability to cross the placenta and infect the fetus. Infection early in gestation with non-cytopathic (ncp) BVDV leads to persistent infection. Establishment of fetal persistent infection results in life-long viremia, virus-specific immunotolerance, and may have detrimental developmental consequences. We have previously shown that heifers infected experimentally with ncp BVDV type 2 on d. 75 of gestation had transient robust up-regulation of the type I interferon (IFN) stimulated genes (ISGs) 3-15 days after viral inoculation. Blood from persistently infected (PI) fetuses, collected 115 days post maternal infection, demonstrated moderate chronic up-regulation of ISGs. This infection model was used to delineate timing of the development of innate immune responses in the fetus and placenta during establishment of persistent infection. It was hypothesized that: (i) chronic stimulation of innate immune responses occurs following infection of the fetus and (ii) placental production of the type I IFN contributes to up-regulation of ISGs in PI fetuses. PI fetuses, generated by intranasal inoculation of pregnant heifers with ncp BVDV, and control fetuses from uninfected heifers, were collected via Cesarean sections on d. 82, 89, 97, 192, and 245 of gestation. Fetal viremia was confirmed starting on d. 89. Significant up-regulation of mRNA encoding cytosolic dsRNA sensors -RIG-I and MDA5 - was detected on d. 82-192. Detection of viral dsRNA by cytosolic sensors leads to the stimulation of ISGs, which was reflected in significant up-regulation of ISG15 mRNA in fetal blood on d. 89, 97, and 192. No difference in IFN-α and IFN-β mRNA concentration was found in fetal blood or caruncular tissue, while a significant increase in both IFN-α and IFN-β mRNA was seen in cotyledons from PI fetuses on d. 192. It is concluded that fetuses respond to early gestational ncp BVDV infection by induction of the type I IFN pathway, resulting in chronic up-regulation of ISGs. Cotyledonary tissue contributes to up-regulation of ISGs by increased production of IFNs. The innate immune response might partially curtail viral replication in PI fetuses, but is not able to eliminate the virus in the absence of a virus-specific adaptive immune response.
胎盘病毒感染取决于胎-胎盘和母体免疫反应之间的复杂相互作用，以及感染发生时胎儿发育的阶段。牛病毒性腹泻病毒（BVDV）能够穿过胎盘并感染胎儿。妊娠早期感染非细胞病变（ncp）BVDV 会导致持续性感染。胎儿持续性感染的建立导致终身病毒血症、病毒特异性免疫耐受，并可能产生不利的发育后果。我们之前已经表明，在妊娠第 75 天用 ncp BVDV 2 型实验感染的小母牛，在病毒接种后 3-15 天内，I 型干扰素（IFN）刺激基因（ISGs）的瞬时强烈上调。从持续性感染（PI）胎儿中采集的血液，在母体感染后 115 天采集，显示出中度慢性 ISG 上调。该感染模型用于描绘在持续性感染建立过程中胎儿和胎盘固有免疫反应的发展时间。假设：（i）胎儿感染后会发生慢性固有免疫反应刺激；（ii）胎盘产生 I 型 IFN 有助于 PI 胎儿中 ISGs 的上调。通过鼻内接种 ncp BVDV 感染怀孕小母牛，生成 PI 胎儿和来自未感染小母牛的对照胎儿，并在妊娠第 82、89、97、192 和 245 天通过剖腹产收集。从妊娠第 89 天开始确认胎儿病毒血症。在妊娠第 82-192 天检测到细胞质 dsRNA 传感器 -RIG-I 和 MDA5 的 mRNA 编码显著上调。细胞质传感器检测到病毒 dsRNA 会导致 ISGs 的刺激，这反映在妊娠第 89、97 和 192 天胎儿血液中 ISG15 mRNA 的显著上调。在胎儿血液或肉阜组织中未发现 IFN-α 和 IFN-β mRNA 浓度的差异，而在妊娠第 192 天 PI 胎儿的胎盘中均观察到 IFN-α 和 IFN-β mRNA 的显著增加。结论是，胎儿通过诱导 I 型 IFN 途径对妊娠早期的 ncp BVDV 感染作出反应，导致 ISGs 的慢性上调。胎盘中的组织通过增加 IFN 的产生有助于 ISGs 的上调。固有免疫反应可能部分抑制 PI 胎儿中的病毒复制，但在没有病毒特异性适应性免疫反应的情况下，无法消除病毒。
