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

Abstract

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 isSuccessful defense against invading pathogens involves rapid recognition of conserved danger signals through members of the Toll-like receptor (TLR) protein family (1) and induction of cytokines that activate both innate and adaptive immunity. A principal effector integrating early antiviral and immunostimulatory activities is the alpha/beta interferon (IFN) system, including the group of IFN-␣ isotypes and IFN-␤ (21). Although most types of cells can produce IFN through recognition of cytosolic double-stranded RNA (1a, 36, 44), or upon stimulation of TLR3 and TLR4 through double-stranded RNA or lipopolysaccharide, respectively (1), the vast amount of IFN upon entry of bacterial and viral pathogens is produced by a specialized cell population, plasmacytoid dendritic cells (PDC) (2, 6). Transcriptional induction of IFN genes is controlled by interferon regulatory factors (IRFs). IRF-3 mainly regulates IFN-␤ induction, whereas IRF-7 has the ability to activate IFN-␣ promoters (22,25,45). In contrast to other cell types, PDC constitutively express high levels of IRF-7 such that expression of IFN-␣ by PDC is independent of the IFN-␣ receptor-mediated positive feedback via IFN-␤ (3, 13, 16, 18), explaining in part the promptness of high-capacity IFN-␣ production.The TLR repertoire of human PDC is composed of TLR7 and TLR9, both located in the endosomal membrane. As shown recently, TLR7 and TLR8 recognize viral singlestranded RNA (8, 12) as well as imidazoquinolines such as imiquimod and resiquimod (R848) and guanosine analogs (reviewed in references 1 and 42). In contrast, TLR9 recognizes bacterial or viral DNA (1), including synthetic CpG oligodeoxynucleotides (ODN) (11). Indeed, recent work revealed IFN-␣ production in PDC after incubation with a variety of inactivated or live DNA and RNA viruses, including herpes simplex virus types 1 and 2 (16,19,23), murine cytomegalovirus (7), human immunodeficiency virus (46), influenza A virus (8,24), Sendai virus (14,16), and vesicular stomatitis virus (3,24). For herpes simplex virus (19,23), Influenza A virus (8,24), and vesicular stomatitis virus (24), the critical involvement of MyD88 adaptor-dependent TLR9 and TLR7 signaling has been demonstrated.In addition to perceiving external virus components through TLR7 and TLR9, human PDC have the means to sense cytosolic replicating RNA viruses. As we could show recently, respiratory syncytial virus (RSV) escapes from recognition by PDC TLRs (14). Nevertheless, infection with a particular laboratory strain of RSV (subtype A, strain Long), or cytosolic delivery of double-stranded RNA but not of poly(I:C) led to potent IFN-␣ induction in PDC in a TLR-and protein kinase R-independent manner (14).The considerable repertoire of tools for sensing pathogens combined with a tremendous capacity to produce IFN make human PDC the key sentinel...

Contribution of cytokines to pathology and protection in virus infection

“…For example, LCMV has been shown to facilitate viral superinfection by impairing IFNαβ production by pDCs and consequently decreasing NK cell activation leading to reduced control and increased early spread of MCMV used as a model for an opportunistic pathogen [47]. This report is in line with previous in vitro findings of efficient suppression of IFNαβ production in human pDCs by measles virus and some strains of RSV, viruses associated with opportunistic infections and pathology [48,49]. In conclusion, the immunomodulatory roles of IFNαβs appear to be as complex as their antiviral roles, and the impact of IFNαβ in viral, bacterial and in co--infections will keep researchers busy for years to come.…”

Gene polymorphisms in Toll-like receptors, interleukin-10, and interleukin-10 receptor alpha and lymphoma risk

“…51 Evidence for a link between measles virus and TLR9 was recently provided. 52 Mice data point towards a critical role of TLR9 in viral sensing.…”

Gene expression patterns in dendritic cells infected with measles virus compared with other pathogens

“…MV induces production of IFN-␣͞␤ by a lung epithelial cell line (30), but there is limited synthesis of IFN by MV-infected PBMCs (31). Plasmacytoid DCs are generally considered to be responsible for early IFN production in response to infection (32), but MV inhibits IFN production by these cells (33). An important early source of IFN in MV infection may be myeloid DCs.…”