Early induction of interferon-responsive mRNAs in Creutzfeldt-Jakob disease.
Foreign infectious agents typically evoke a host immune response. In scrapie and Creutzfeldt-Jakob disease (CJD), no immune response has been detectable. However, many latent or persistent viruses evade immune recognition but still activate inflammatory pathways. Unique microglial responses in late CJD infection that could be part of a host defense mechanism were previously delineated, although changes secondary to neurodegeneration could not be excluded. Data here show these microglial transcriptional changes are detectable in CJD brain beginning at 30 days after innoculation. In addition, 10 other interferon-sensitive genes were similarly upregulated at very early stages of infection. These responses occurred well before abnormal prion protein (PrP) and clinical signs of CJD were detectable. Further analyses in very pure microglia from CJD brain suggested the CJD agent activated signaling pathways distinct from those induced by amyloidogenic proteins (including abnormal PrP). Although increases in interferon-alpha or -beta transcript levels were not seen in cultures or in whole brain, CJD microglia exhibited a potentiated interferon response when challenged with double-stranded RNA. The induction of interferon-sensitive genes without appreciable interferon synthesis was strikingly similar to that seen in some viral infections. These data suggest the CJD agent is recognized as a foreign virus-like entity. Moreover, the early reactive gene expression profiles described here may be useful in preclinical diagnosis.
Baker
Christopher A
CA
Section of Neuropathology, Yale School of Medicine, New Haven, Connecticut, USA.
Lu
Zhi Yun
ZY
Manuelidis
Laura
L
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D016000:Cluster Analysis; D007562:Creutzfeldt-Jakob Syndrome / Q000235:genetics* / Q000276:immunology; D017931:DNA Primers; D005786:Gene Expression Regulation; D007372:Interferons / Q000235:genetics*; D051379:Mice; D017628:Microglia / Q000378:metabolism*; D018620:PrPSc Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation
D017931:DNA Primers; D018620:PrPSc Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D007372:Interferons