Proteolysis of MDA5 and IPS-1 is not required for inhibition of the type I IFN response by poliovirus.

Swathi Kotla,Kurt E Gustin

doi:10.1186/s12985-015-0393-2

Swathi Kotla, Kurt E Gustin

Open Access

https://doi.org/10.1186/s12985-015-0393-2

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Abstract

BackgroundThe type I interferon (IFN) response is a critical component of the innate immune response to infection by RNA viruses and is initiated via recognition of viral nucleic acids by RIG-like receptors (RLR). Engagement of these receptors in the cytoplasm initiates a signal transduction pathway leading to activation of the transcription factors NF-κB, ATF-2 and IRF-3 that coordinately upregulate transcription of type I IFN genes, such as that encoding IFN-β. In this study the impact of poliovirus infection on the type I interferon response has been examined.MethodsThe type I IFN response was assessed by measuring IFN-β mRNA levels using qRT-PCR and normalizing to levels of β-actin mRNA. The status of host factors involved in activation of the type I IFN response was examined by immunoblot, immunofluorescence microcopy and qRT-PCR.ResultsThe results show that poliovirus infection results in induction of very low levels of IFN-β mRNA despite clear activation of NF-κB and ATF-2. In contrast, analysis of IRF-3 revealed no transcriptional induction of an IRF-3-responsive promoter or homodimerization of IRF-3 indicating it is not activated in poliovirus-infected cells. Exposure of poliovirus-infected cells to poly(I:C) results in lower levels of IFN-β mRNA synthesis and IRF-3 activation compared to mock-infected cells. Analysis of MDA-5 and IPS-1 revealed that these components of the RLR pathway were largely intact at times when the type I IFN response was suppressed.ConclusionsCollectively, these results demonstrate that poliovirus infection actively suppresses the host type I interferon response by blocking activation of IRF-3 and suggests that this is not mediated by cleavage of MDA-5 or IPS-1.

Highlights

Picornaviruses are small, positive sense, single-stranded RNA viruses belonging to the family Picornaviridae
Activation of RIG-like receptors (RLR) and TLRs initiates distinct signaling pathways that converge on the cellular transcription factors NF-κB, IRF-3 and ATF-2 which are required for the induction of IFN-β mRNA and the type I interferon response [4]
Poliovirus-infected cells showed only a 2 fold increase in IFN-β mRNA levels at 3 and 4 h post infection and by 5 hpi levels were very similar to mockinfected controls (Fig. 1)

Summary

Introduction

Picornaviruses are small, positive sense, single-stranded RNA viruses belonging to the family Picornaviridae. Activation of RLRs and TLRs initiates distinct signaling pathways that converge on the cellular transcription factors NF-κB, IRF-3 and ATF-2 which are required for the induction of IFN-β mRNA and the type I interferon response [4]. The type I interferon (IFN) response is a critical component of the innate immune response to infection by RNA viruses and is initiated via recognition of viral nucleic acids by RIG-like receptors (RLR). Engagement of these receptors in the cytoplasm initiates a signal transduction pathway leading to activation of the transcription factors NF-κB, ATF-2 and IRF-3 that coordinately upregulate transcription of type I IFN genes, such as that encoding IFN-β. In this study the impact of poliovirus infection on the type I interferon response has been examined

Methods

Results

Conclusion