Inhibition of Type III Interferon Expression in Intestinal Epithelial Cells-A Strategy Used by Coxsackie B Virus to Evade the Host's Innate Immune Response at the Primary Site of Infection?

Virginia M Stone,Malin Flodström-Tullberg,Erna Domsgen,Pär G Larsson,Emma E Ringqvist,Ulrika Holmlund,Eva Sverremark-Ekström

doi:10.3390/microorganisms9010105

Virginia M Stone, Malin Flodström-Tullberg + Show 5 more

Open Access

https://doi.org/10.3390/microorganisms9010105

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Abstract

Increasing evidence highlights the importance of the antiviral activities of the type III interferons (IFNλs; IL-28A, IL-28B, IL29, and IFNλ4) in the intestine. However, many viruses have developed strategies to counteract these defense mechanisms by preventing the production of IFNs. Here we use infection models, a clinical virus isolate, and several molecular biology techniques to demonstrate that both type I and III IFNs induce an antiviral state and attenuate Coxsackievirus group B (CVB) replication in human intestinal epithelial cells (IECs). While treatment of IECs with a viral mimic (poly (I:C)) induced a robust expression of both type I and III IFNs, no such up-regulation was observed after CVB infection. The blunted IFN response was paralleled by a reduction in the abundance of proteins involved in the induction of interferon gene transcription, including TIR-domain-containing adapter-inducing interferon-β (TRIF), mitochondrial antiviral-signaling protein (MAVS), and the global protein translation initiator eukaryotic translation initiation factor 4G (eIF4G). Taken together, this study highlights a potent anti-Coxsackieviral effect of both type I and III IFNs in cells located at the primary site of infection. Furthermore, we show for the first time that the production of type I and III IFNs in IECs is blocked by CVBs. These findings suggest that CVBs evade the host immune response in order to successfully infect the intestine.

Highlights

The gastrointestinal tract plays a critical role in preventing infections by invading pathogens, such as viruses, we are only just beginning to understand the details regarding how the interplay between the host, the commensal microbiota, and infecting microbes dictates permissiveness and susceptibility to infection.Type I (α, β, ε, κ, ω) and type III (λ-1, -2, -3 and -4) interferons (IFNs) are key components of the host’s innate immune response to viruses
These results suggest that Coxsackievirus B3 (CVB3) cleaves the proteins eukaryotic initiation factor 4G (eIF4G), mitochondrial antiviral-signaling protein (MAVS), and TIR-domain-containing adaptor-inducing interferon-β (TRIF) in intestinal epithelial cells (IECs), which are involved in global protein from translation andlines interferon production
We examined whether the expression of the downstream signaling proteins MAVS and TRIF are altered after CVB3 infection in IECs [38,39,40,41]

Summary

Introduction

Type I (α, β, ε, κ, ω) and type III (λ-1, -2, -3 and -4) interferons (IFNs) are key components of the host’s innate immune response to viruses. IFN-mediated protection against viruses is elicited through the induced expression of a number of interferon-stimulated genes (ISGs), which encode proteins that promote an anti-viral state. Type I and III IFNs elicit similar anti-viral responses. Type I IFNs protect intestinal epithelial cells (IECs) against a variety of enteric viruses and more recently, an anti-viral role of the type III IFNs has been described. Despite the similarities between type I and III IFNs, recent studies have identified a non-redundant, sterilizing effect of the type III IFNs in the intestine against certain enteric viruses, highlighting a potentially important, organ specific role of these cytokines [3,4,5]

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