Department of Pediatric and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Southeast Poultry Research Laboratory, US National Poultry Research Center, United States Department of Agriculture (USDA-ARS), Athens, Georgia, USA.
J Interferon Cytokine Res. 2023 Sep;43(9):427-434. doi: 10.1089/jir.2023.0046.
Biliary atresia (BA) is a life-threatening cholangiopathy occurring in infancy, the most common indication for pediatric liver transplantation. The etiology of BA remains unknown; however, a viral etiology has been proposed as multiple viruses have been detected in explants of infants afflicted with BA. In the murine model of BA, Rhesus rotavirus (RRV) infection of newborn BALB/c pups results in a cholangiopathy that mirrors human BA. Infected BALB/c pups experience 100% symptomatology and mortality, while C57BL/6 mice are asymptomatic. Interferon-λ (IFN-λ) is an epithelial cytokine that provides protection against viral infection. We demonstrated that IFN-λ is highly expressed in C57BL/6, leading to reduced RRV replication. RRV-infection of C57BL/6 IFN-λ receptor knockout (C57BL/6 IFN-λR KO) pups resulted in 90% developing obstructive symptoms and 45% mortality with a higher viral titer in bile ducts and profound periportal inflammation compared to C57BL/6. Histology revealed complete biliary obstruction in symptomatic C57BL/6 IFN-λR KO pups, while C57BL/6 ducts were patent. These findings suggest that IFN-λ is critical in preventing RRV replication. Deficiency in IFN-λ permits RRV infection, which triggers the inflammatory cascade causing biliary obstruction. Further IFN-λ study is warranted as it may play an important role in infant susceptibility to BA.
先天性胆道闭锁（BA）是一种危及生命的婴儿期胆管病，是小儿肝移植最常见的适应证。BA 的病因尚不清楚；然而，已经提出了病毒病因，因为在患有 BA 的婴儿的移植标本中已经检测到多种病毒。在 BA 的鼠模型中，恒河猴轮状病毒（RRV）感染新生 BALB/c 幼仔会导致类似于人类 BA 的胆管病。受感染的 BALB/c 幼仔 100%出现症状和死亡，而 C57BL/6 小鼠无症状。干扰素-λ（IFN-λ）是一种上皮细胞因子，可提供针对病毒感染的保护。我们证明 IFN-λ在 C57BL/6 中高度表达，导致 RRV 复制减少。RRV 感染 C57BL/6 IFN-λ 受体敲除（C57BL/6 IFN-λR KO）幼仔导致 90%出现阻塞症状和 45%死亡，胆管中的病毒滴度更高，门脉周围炎症更严重与 C57BL/6 相比。组织学显示，有症状的 C57BL/6 IFN-λR KO 幼仔的胆管完全阻塞，而 C57BL/6 胆管通畅。这些发现表明 IFN-λ对于防止 RRV 复制至关重要。IFN-λ 缺乏允许 RRV 感染，从而引发导致胆管阻塞的炎症级联反应。进一步研究 IFN-λ 是必要的，因为它可能在婴儿易患 BA 方面发挥重要作用。
