The alpha/beta interferon receptor provides protection against influenza virus replication but is dispensable for inflammatory response signaling.
The innate immune response provides the first line of defense against foreign pathogens by responding to molecules that are a signature of a pathogenic infection. Certain RNA viruses, such as influenza virus, produce double-stranded RNA as an intermediate during the replication life cycle, which activates pathogen recognition receptors capable of inducing interferon production. By engaging interferon receptors, interferon activates the JAK-STAT pathway and results in the positive feedback of interferon production, amplifying the response to viral infection. To examine how deficiencies in interferon signaling affect the cellular response to infection, we performed influenza virus infections of mouse embryonic fibroblasts lacking the alpha/beta interferon receptor, the gamma interferon receptor, or both. In the absence of the alpha/beta interferon receptor, we observed increased viral replication but decreased activation of PKR, Stat1, and NF-kappaB; the presence or absence of the gamma interferon receptor did not exhibit discernible differences in these readouts. Analysis of gene expression profiles showed that while cells lacking the alpha/beta interferon receptor exhibited decreased levels of transcription of antiviral genes, genes related to inflammatory and apoptotic responses were transcribed to levels similar to those of cells containing the receptor. These results indicate that while the alpha/beta interferon receptor is needed to curb viral replication, it is dispensable for the induction of certain inflammatory and apoptotic genes. We have identified potential pathways, via interferon regulatory factor 3 (IRF3) activation or Hoxa13, Polr2a, Nr4a1, or Ing1 induction, that contribute to this redundancy. This study illustrates another way in which the host has evolved to establish several overlapping mechanisms to respond to viral infections.
Goodman
Alan G
AG
Department of Microbiology, University of Washington, Box 358070, Seattle, WA 98195-8070, USA.
Zeng
Hui
H
Proll
Sean C
SC
Peng
Xinxia
X
Cillóniz
Cristian
C
Carter
Victoria S
VS
Korth
Marcus J
MJ
Tumpey
Terrence M
TM
Katze
Michael G
MG
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D002478:Cells, Cultured; D004279:DNA, Viral / Q000235:genetics; D004285:Dogs; D054884:Host-Pathogen Interactions / Q000276:immunology; D007249:Inflammation / Q000276:immunology / Q000821:virology; D009980:Influenza A virus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D014774:Virulence; D014779:Virus Replication / Q000276:immunology*; D019892:eIF-2 Kinase / Q000378:metabolism
D004279:DNA, Viral; D016328:NF-kappa B; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D053633:Receptor, Interferon alpha-beta; D019892:eIF-2 Kinase