Flavivirus activation of plasmacytoid dendritic cells delineates key elements of TLR7 signaling beyond endosomal recognition.
TLR7 senses RNA in endosomal compartments. TLR7 expression and signaling have been demonstrated in plasmacytoid and myeloid dendritic cells, B cells, and T cells. The regulation of TLR7 signaling can play a crucial role in shaping the immune response to RNA viruses with different cellular tropisms, and in developing adjuvants capable of promoting balanced humoral and cell-mediated immunity. We used unique characteristics of two ssRNA viruses, dengue virus and influenza virus, to delineate factors that regulate viral RNA-human TLR7 signaling beyond recognition in endosomal compartments. Our data show that TLR7 recognition of enveloped RNA virus genomes is linked to virus fusion or uncoating from the endosome. The signaling threshold required to activate TLR7-type I IFN production is greater than that required to activate TLR7-NF-kappaB-IL-8 production. The higher order structure of viral RNA appears to be an important determinant of TLR7-signaling potency. A greater understanding of viral RNA-TLR7 activity relationships will promote rational approaches to interventional and vaccine strategies for important human viral pathogens.
Wang
Jennifer P
JP
Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA. jennifer.wang@umassmed.edu
Liu
Ping
P
Latz
Eicke
E
Golenbock
Douglas T
DT
Finberg
Robert W
RW
Libraty
Daniel H
DH
D000328:Adult; D000818:Animals; D002460:Cell Line; D003713:Dendritic Cells / Q000378:metabolism* / Q000648:ultrastructure / Q000821:virology*; D003716:Dengue Virus / Q000235:genetics / Q000502:physiology* / Q000648:ultrastructure; D004285:Dogs; D011992:Endosomes / Q000378:metabolism* / Q000821:virology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009980:Influenza A virus / Q000502:physiology*; D016898:Interferon-alpha / Q000096:biosynthesis / Q000378:metabolism; D016209:Interleukin-8 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000096:biosynthesis; D012367:RNA, Viral / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014760:Viral Fusion Proteins / Q000502:physiology; D014775:Virus Activation / Q000502:physiology
D016898:Interferon-alpha; D016209:Interleukin-8; D016328:NF-kappa B; D012367:RNA, Viral; D051199:Toll-Like Receptor 7; D014760:Viral Fusion Proteins