A paradox of transcriptional and functional innate interferon responses of human intestinal enteroids to enteric virus infection

Kapil Saxena, Lukas M. Simon, Xi Lei Zeng, Sarah E. Blutt, Sue E. Crawford, Narayan P. Sastri, Umesh C. Karandikar, Nadim J. Ajami, Nicholas C. Zachos, Olga Kovbasnjuk, Mark Donowitz, Margaret E. Conner, Chad A. Shaw, Mary K. Estes

Research output: Contribution to journalArticle

Abstract

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 frommultiple individuals with human rotavirus (HRV) and assessed the host epithelial response by using RNAsequencing 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.

Original languageEnglish (US)
Pages (from-to)E570-E579
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number4
DOIs
StatePublished - Jan 24 2017

Keywords

  • Enteric virus
  • Human enteroids
  • Human rotavirus
  • Interferon

ASJC Scopus subject areas

  • General

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