title: Proteolysis of MDA5 and IPS-1 is not required for inhibition of the type I IFN response by poliovirus.
abstract: BACKGROUND
  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
  The 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.
  
  
  RESULTS
  The 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.
  
  
  CONCLUSIONS
  Collectively, 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.
authors.affiliation: Present address: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. swathi_kotla2001@yahoo.com.
authors.forename: Swathi
authors.initials: S
authors.lastname: Kotla
authors.affiliation: Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, 85004, USA. kgustin@email.arizona.edu.
authors.forename: Kurt E
authors.initials: KE
authors.lastname: Gustin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D002460:Cell Line; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D020869:Gene Expression Profiling; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D007113:Immunity, Innate; D015151:Immunoblotting; D050838:Interferon Regulatory Factor-3 / Q000037:antagonists & inhibitors*; D000072640:Interferon-Induced Helicase, IFIH1; D016899:Interferon-beta / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D008856:Microscopy, Fluorescence; D017955:Poliovirus / Q000276:immunology* / Q000502:physiology*; D059748:Proteolysis; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D050838:Interferon Regulatory Factor-3; C505371:MAVS protein, human; D012333:RNA, Messenger; D016899:Interferon-beta; C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1