Saxena Kapil, Simon Lukas M, Zeng Xi-Lei, Blutt Sarah E, Crawford Sue E, Sastri Narayan P, Karandikar Umesh C, Ajami Nadim J, Zachos Nicholas C, Kovbasnjuk Olga, Donowitz Mark, Conner Margaret E, Shaw Chad A, Estes Mary K
Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030.
Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, TX 77030.
Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E570-E579. doi: 10.1073/pnas.1615422114. Epub 2017 Jan 9.
The intestinal epithelium can limit enteric pathogens by producing antiviral cytokines, such as IFNs. Type I IFN (IFN-α/β) and type III IFN (IFN-λ) function at the epithelial level, and their respective efficacies depend on the specific pathogen and site of infection. However, the roles of type I and type III IFN in restricting human enteric viruses are poorly characterized as a result of the difficulties in cultivating these viruses in vitro and directly obtaining control and infected small intestinal human tissue. We infected nontransformed human intestinal enteroid cultures from multiple individuals with human rotavirus (HRV) and assessed the host epithelial response by using RNA-sequencing and functional assays. The dominant transcriptional pathway induced by HRV infection is a type III IFN-regulated response. Early after HRV infection, low levels of type III IFN protein activate IFN-stimulated genes. However, this endogenous response does not restrict HRV replication because replication-competent HRV antagonizes the type III IFN response at pre- and posttranscriptional levels. In contrast, exogenous IFN treatment restricts HRV replication, with type I IFN being more potent than type III IFN, suggesting that extraepithelial sources of type I IFN may be the critical IFN for limiting enteric virus replication in the human intestine.
肠道上皮细胞可通过产生抗病毒细胞因子（如干扰素）来限制肠道病原体。I型干扰素（IFN-α/β）和III型干扰素（IFN-λ）在上皮水平发挥作用，它们各自的功效取决于特定的病原体和感染部位。然而，由于在体外培养这些病毒以及直接获取对照和感染的人小肠组织存在困难，I型和III型干扰素在限制人类肠道病毒方面的作用尚未得到充分表征。我们用人类轮状病毒（HRV）感染了来自多个个体的未转化的人肠道类器官培养物，并通过RNA测序和功能分析评估了宿主上皮反应。HRV感染诱导的主要转录途径是III型干扰素调节的反应。HRV感染后早期，低水平的III型干扰素蛋白激活干扰素刺激基因。然而，这种内源性反应并不能限制HRV复制，因为具有复制能力的HRV在转录前和转录后水平拮抗III型干扰素反应。相比之下，外源性干扰素治疗可限制HRV复制，I型干扰素比III型干扰素更有效，这表明I型干扰素的上皮外来源可能是限制人类肠道中肠道病毒复制的关键干扰素。
