Establishment and maintenance of the innate antiviral response to West Nile Virus involves both RIG-I and MDA5 signaling through IPS-1.
RIG-I and MDA5, two related pathogen recognition receptors (PRRs), are known to be required for sensing various RNA viruses. Here we investigated the roles that RIG-I and MDA5 play in eliciting the antiviral response to West Nile virus (WNV). Functional genomics analysis of WNV-infected fibroblasts from wild-type mice and RIG-I null mice revealed that the normal antiviral response to this virus occurs in two distinct waves. The initial response to WNV resulted in the expression of interferon (IFN) regulatory factor 3 target genes and IFN-stimulated genes, including several subtypes of alpha IFN. Subsequently, a second phase of IFN-dependent antiviral gene expression occurred very late in infection. In cells lacking RIG-I, both the initial and the secondary responses to WNV were delayed, indicating that RIG-I plays a critical role in initiating innate immunity against WNV. However, another PRR(s) was able to trigger a response to WNV in the absence of RIG-I. Disruption of both MDA5 and RIG-I pathways abrogated activation of the antiviral response to WNV, suggesting that MDA5 is involved in the host's defense against WNV infection. In addition, ablation of the function of IPS-1, an essential RIG-I and MDA5 adaptor molecule, completely disabled the innate antiviral response to WNV. Our data indicate that RIG-I and MDA5 are responsible for triggering downstream gene expression in response to WNV infection by signaling through IPS-1. We propose a model in which RIG-I and MDA5 operate cooperatively to establish an antiviral state and mediate an IFN amplification loop that supports immune effector gene expression during WNV infection.
Fredericksen
Brenda L
BL
Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA. bfreder@umd.edu
Keller
Brian C
BC
Fornek
Jamie
J
Katze
Michael G
MG
Gale
Michael
M
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000172:deficiency / Q000276:immunology*; D005347:Fibroblasts / Q000821:virology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D007113:Immunity, Innate; D000072640:Interferon-Induced Helicase, IFIH1; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction; D014901:West Nile Fever / Q000276:immunology; D014902:West Nile virus / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1; C512612:MAVS protein, mouse; C503356:Ddx58 protein, mouse; C510592:Ifih1 protein, mouse