Interferon-β Pretreatment of Conventional and Plasmacytoid Human Dendritic Cells Enhances Their Activation by Influenza Virus

Phipps-Yonas, Hannah; Seto, Jeremy; Sealfon, Stuart C.; Moran, Thomas M.; Fernández-Sesma, Ana

doi:10.1371/journal.ppat.1000193

Cited by 68 publications

(65 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…DENV-2 (16681 and NGC strains) and DENV-3 (Hawaii strain) were grown in C6/36 insect cells (5) and were titrated by plaque assay (4). moDCs were infected with DENV-2 at different multiplicities of infection (MOIs), and viral replication was tested by quantitative reverse transcription-PCR (qRT-PCR) (9,28). All infections in this study were performed in moDCs from at least three independent donors with three replicates per sample.…”

mentioning

confidence: 99%

Dengue Virus Inhibits the Production of Type I Interferon in Primary Human Dendritic Cells

Rodríguez-Madoz

Bernal-Rubio

Kaminski

et al. 2010

J Virol

Self Cite

125

View full text Add to dashboard Cite

Dengue virus (DENV) infects human immune cells in vitro and likely infects dendritic cells (DCs) in vivo.DENV-2 productive infection induces activation and release of high levels of chemokines and proinflammatory cytokines in monocyte-derived DCs (moDCs), with the notable exception of alpha/beta interferon (IFN-␣/␤). Interestingly, DENV-2-infected moDCs fail to prime T cells, most likely due to the lack of IFN-␣/␤ released by moDCs, since this effect was reversed by addition of exogenous IFN-␤. Together, our data show that inhibition of IFN-␣/␤ production by DENV in primary human moDCs is a novel mechanism of immune evasion.Dengue virus (DENV) belongs to the family Flaviviridae and has great importance in the areas of medicine and biodefense (3,17). Transmitted by Aedes aegypti, DENV is the most prevalent arthropod-borne human virus (34). Generally, infected patients experience dengue fever, but 2 to 20% of cases manifest dengue hemorrhagic fever (DHF), a severe and often lethal illness (34). Dendritic cells (DCs) initiate immune responses and become activated upon contact with pathogens (2), with upregulation of costimulatory molecules and release of proinflammatory cytokines (2). Secretion of type I interferon (alpha/beta interferon [IFN-␣/␤]) by DCs contributes to the generation of antiviral innate and adaptive immune responses (7,16,18,32). DCs, together with other cell populations, have been suggested as target cells for DENV infection (12,14,15,35).We investigated the replication of DENV-2 in monocytederived DCs (moDCs) obtained by culturing CD14 ϩ cells, isolated from blood of healthy donors, for 6 days in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 4 (IL-4), and human serum (9). The purity obtained by flow cytometry was routinely 96 to 99% CD14 Ϫ CD11c ϩ HLA-DR low moDCs (7). DENV-2 (16681 and NGC strains) and DENV-3 (Hawaii strain) were grown in C6/36 insect cells (5) and were titrated by plaque assay (4). moDCs were infected with DENV-2 at different multiplicities of infection (MOIs), and viral replication was tested by quantitative reverse transcription-PCR (qRT-PCR) (9, 28). All infections in this study were performed in moDCs from at least three independent donors with three replicates per sample. DENV-2 replication peaked at 48 h after infection (Fig. 1A), and release of newly synthesized infectious particles had a similar kinetics (Fig. 1B), indicating productive infection of moDCs. As a measure of moDC activation, proinflammatory cytokine levels (IL-6 and tumor necrosis factor alpha [TNF-␣]) were quantified by enzyme-linked immunosorbent assay (ELISA) 24 h after DENV-2 infection (Fig. 1C). We observed high expression of those cytokines, comparable to cytokine expression after poly(I:C) treatment of moDCs. Interestingly, UV-inactivated DENV-2 did not induce the moDC activation, suggesting that DENV-2 replication is required to activate moDCs. Infection with influenza virus A/PR8/33 (PR8) showed low levels of cytokine induction due to the activity of the N...

show abstract

mentioning

confidence: 99%

Dengue Virus Inhibits the Production of Type I Interferon in Primary Human Dendritic Cells

Rodríguez-Madoz

Bernal-Rubio

Kaminski

et al. 2010

J Virol

Self Cite

125

View full text Add to dashboard Cite

show abstract

“…These low levels of IRAK-1 may be sufficient, in the presence of an enhancing factor, to mediate the increased IFN-a response seen at early time points after TLR7 stimulation. Type I IFN, which is increased in serum for up to 6 hours after TLR7 stimulation, may represent such an amplification factor of IFN-a (22). IRAK-1 is not involved in TLR-dependent proinflammatory cytokine release by plasmacytoid DCs (7), suggesting that IRAK-1 degradation is not responsible for the hyporesponsiveness affecting IL-6 and IL-12.…”

Section: Discussionmentioning

confidence: 99%

“…The increased production of IFN-a seen when mice were restimulated with R848 at an early time point after the first injection ( Fig. 1) may result from a priming effect of type I IFN (22). Indeed, pDCs prestimulated with recombinant IFN-a show enhanced secondary IFN-a secretion following R848 stimulation (Fig.…”

Section: Prestimulation With R848 Leads To Degradation Of Irak-1 In Pmentioning

confidence: 98%

Systemic Cancer Therapy with a Small Molecule Agonist of Toll-like Receptor 7 Can Be Improved by Circumventing TLR Tolerance

et al. 2011

View full text Add to dashboard Cite

Topical application of small molecule Toll-like receptor 7 (TLR7) agonists is highly effective for the treatment of skin tumors, whereas their systemic application has been largely unsuccessful for cancer therapy. One reason may be that repeated systemic application of TLR ligands can induce a state of immune unresponsiveness, termed TLR tolerance. We show here that a single injection of the TLR7 agonist R848 in mice induces a short period of increased response to TLR stimulation followed by a state of hyporesponsiveness lasting several days. This state is characterized by inhibited secretion of the key cytokines interleukin (IL)-12p70 and IL-6 as well as by a block in IFN-a production. We show for the first time that at the cellular level, TLR7 tolerance occurs in both plasmacytoid and myeloid dendritic cells, two cell populations that play a critical role in the initiation and amplification of antitumor immune responses. We further show that TLR7 tolerance in plasmacytoid dendritic cells is accompanied by downregulation of the adaptor protein IL-1 receptor-associated kinase 1. On the basis of these findings, we have designed a novel strategy for the treatment of tumors by using cycles of repeated R848 injections separated by treatment-free intervals. We show in CT26 tumor-bearing mice that this protocol circumvents TLR7 tolerance and improves the efficacy of cancer immunotherapy. Cancer Res; 71(15); 5123-33. Ó2011 AACR.

show abstract

“…However, DCs or monocytes exposed to type I IFNs and other inflammatory cytokines are protected against uncontrolled virus infection and gain the capacity to respond vigorously to the virus even in the presence of NS1 (19,20). Thus, the concentration of inflammatory cytokines in the lungs and blood stream of infected animals is rapidly increased when the preactivated cells respond to virus.…”

Section: Discussionmentioning

confidence: 99%

Cutting Edge: Stealth Influenza Virus Replication Precedes the Initiation of Adaptive Immunity

Moltedo

López

Pazos

et al. 2009

The Journal of Immunology

Self Cite

102

View full text Add to dashboard Cite

A timely immune response is crucial for the effective control of virus infection. The influenza virus NS1 protein interferes with the expression of key proinflammatory cytokines from infected cells in vitro. To investigate the effect of NS1 during the onset of immunity in vivo, we systematically studied the early events that occur in the lungs and draining lymph nodes upon infection with influenza virus. Strikingly, no sign of innate immunity was detected in the lungs for almost 2 days after infection until a sudden inflammatory burst, including IFNs, cytokines, and chemokines, occurred. This burst preceded the robust dendritic cell migration and T cell activation in the lymph nodes. An NS1-deficient virus triggered rapid inflammation in the lungs whereas a wild-type virus did not. Thus, we demonstrate that, in vivo, influenza virus uses the NS1 protein to replicate for almost 2 days after infection before detection by the immune system.

show abstract

Interferon-β Pretreatment of Conventional and Plasmacytoid Human Dendritic Cells Enhances Their Activation by Influenza Virus

Cited by 68 publications

References 40 publications

Dengue Virus Inhibits the Production of Type I Interferon in Primary Human Dendritic Cells

Dengue Virus Inhibits the Production of Type I Interferon in Primary Human Dendritic Cells

Systemic Cancer Therapy with a Small Molecule Agonist of Toll-like Receptor 7 Can Be Improved by Circumventing TLR Tolerance

Cutting Edge: Stealth Influenza Virus Replication Precedes the Initiation of Adaptive Immunity

Contact Info

Product

Resources

About