Inhibition of toll-like receptor 7- and 9-mediated alpha/beta interferon production in human plasmacytoid dendritic cells by respiratory syncytial virus and measles virus.
Human plasmacytoid dendritic cells (PDC) are key sentinels alerting both innate and adaptive immune responses through production of huge amounts of alpha/beta interferon (IFN). IFN induction in PDC is triggered by outside-in signal transduction pathways through Toll-like receptor 7 (TLR7) and TLR9 as well as by recognition of cytosolic virus-specific patterns. TLR7 and TLR9 ligands include single-stranded RNA and CpG-rich DNA, respectively, as well as synthetic derivatives thereof which are being evaluated as therapeutic immune modulators promoting Th1 immune responses. Here, we identify the first viruses able to block IFN production by PDC. Both TLR-dependent and -independent IFN responses are abolished in human PDC infected with clinical isolates of respiratory syncytial virus (RSV), RSV strain A2, and measles virus Schwarz, in contrast to RSV strain Long, which we previously identified as a potent IFN inducer in human PDC (Hornung et al., J. Immunol. 173:5935-5943, 2004). Notably, IFN synthesis of PDC activated by the TLR7 and TLR9 agonists resiquimod (R848) and CpG oligodeoxynucleotide 2216 is switched off by subsequent infection by RSV A2 and measles virus. The capacity of RSV and measles virus of human PDC to shut down IFN production should contribute to the characteristic features of these viruses, such as Th2-biased immune pathology, immune suppression, and superinfection.
Schlender
Jörg
J
Max-von-Pettenkofer Institute and Gene Center, Feodor-Lynen-Str. 25, D-81377 Munich, Germany. conzelma@lmb.uni-muenchen.de.
Hornung
Veit
V
Finke
Stefan
S
Günthner-Biller
Margit
M
Marozin
Sabrina
S
Brzózka
Krzysztof
K
Moghim
Sharareh
S
Endres
Stefan
S
Hartmann
Gunther
G
Conzelmann
Karl-Klaus
KK
D003713:Dendritic Cells / Q000276:immunology / Q000821:virology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D016898:Interferon-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D016899:Interferon-beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008459:Measles virus / Q000276:immunology / Q000472:pathogenicity*; D008562:Membrane Glycoproteins / Q000819:agonists / Q000037:antagonists & inhibitors*; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000819:agonists / Q000037:antagonists & inhibitors*; D012136:Respiratory Syncytial Viruses / Q000276:immunology / Q000472:pathogenicity*; D013997:Time Factors; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors
C408982:CPG-oligonucleotide; D007093:Imidazoles; D016898:Interferon-alpha; D008562:Membrane Glycoproteins; D009838:Oligodeoxyribonucleotides; D011956:Receptors, Cell Surface; C495348:TLR7 protein, human; C495371:TLR9 protein, human; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D016899:Interferon-beta; C402365:resiquimod