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


ABSTRACT: The intestinal epithelium can limit enteric pathogens by producing antiviral cytokines, such as IFNs. Type I IFN (IFN-?/?) and type III IFN (IFN-?) 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.

SUBMITTER: Saxena K 

PROVIDER: S-EPMC5278484 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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

Saxena Kapil K   Simon Lukas M LM   Zeng Xi-Lei XL   Blutt Sarah E SE   Crawford Sue E SE   Sastri Narayan P NP   Karandikar Umesh C UC   Ajami Nadim J NJ   Zachos Nicholas C NC   Kovbasnjuk Olga O   Donowitz Mark M   Conner Margaret E ME   Shaw Chad A CA   Estes Mary K MK  

Proceedings of the National Academy of Sciences of the United States of America 20170109 4


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 int  ...[more]

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