Early Alpha/Beta Interferon Production by Myeloid Dendritic Cells in Response to UV-Inactivated Virus Requires Viral Entry and Interferon Regulatory Factor 3 but Not MyD88

Hidmark, Åsa; McInerney, Gerald M.; Nordström, Erik; Douagi, Iyadh; Werner, Kristen M.; Liljeström, Peter; Hedestam, Gunilla B. Karlsson

doi:10.1128/jvi.79.16.10376-10385.2005

Cited by 58 publications

(68 citation statements)

References 78 publications

(116 reference statements)

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“…The DREP platform differs from conventional DNA plasmids in that it encodes the alphavirus (CHIKV) replicase, which drives the production of the subgenomic RNA and thus the expression of the encoded CHIKV antigen. Moreover, DREPs also possess intrinsic adjuvant properties, since the replicase and RNA intermediates stimulate the production of type 1 interferons (IFNs) and apoptosis (32)(33)(34). Promising results have been reported for DNA replicons generated from other alphaviruses, including Semliki Forest virus (35)(36)(37), Sindbis virus (38,39), and Venezuelan equine encephalitis virus (40), when they are used for priming immunizations prior to boosting with other vaccine modalities (36).…”

Section: Hikungunya Virus (Chikv) Is An Alphavirus Of the Familymentioning

confidence: 82%

Prime-Boost Immunization Strategies against Chikungunya Virus

Holzmann

Lum

Kümmerer

et al. 2014

J Virol

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Chikungunya virus (CHIKV) is a reemerging mosquito-borne alphavirus that causes debilitating arthralgia in humans. Here we describe the development and testing of novel DNA replicon and protein CHIKV vaccine candidates and evaluate their abilities to induce antigen-specific immune responses against CHIKV. We also describe homologous and heterologous prime-boost immunization strategies using novel and previously developed CHIKV vaccine candidates. Immunogenicity and efficacy were studied in a mouse model of CHIKV infection and showed that the DNA replicon and protein antigen were potent vaccine candidates, particularly when used for priming and boosting, respectively. Several prime-boost immunization strategies eliciting unmatched humoral and cellular immune responses were identified. Further characterization by antibody epitope mapping revealed differences in the qualitative immune responses induced by the different vaccine candidates and immunization strategies. Most vaccine modalities resulted in complete protection against wild-type CHIKV infection; however, we did identify circumstances under which certain immunization regimens may lead to enhancement of inflammation upon challenge. These results should help guide the design of CHIKV vaccine studies and will form the basis for further preclinical and clinical evaluation of these vaccine candidates. IMPORTANCE As of today, there is no licensed vaccine to prevent CHIKV infection. In considering potential new vaccine candidates, a vaccinethat could raise long-term protective immunity after a single immunization would be preferable. While humoral immunity seems to be central for protection against CHIKV infection, we do not yet fully understand the correlates of protection. Therefore, in the absence of a functional vaccine, there is a need to evaluate a number of different candidates, assessing their merits when they are used either in a single immunization or in a homologous or heterologous prime-boost modality. Here we show that while single immunization with various vaccine candidates results in potent responses, combined approaches significantly enhance responses, suggesting that such approaches need to be considered in the further development of an efficacious CHIKV vaccine.

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Section: Hikungunya Virus (Chikv) Is An Alphavirus Of the Familymentioning

confidence: 82%

Prime-Boost Immunization Strategies against Chikungunya Virus

Holzmann

Lum

Kümmerer

et al. 2014

J Virol

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“…Recent results from our laboratory have indeed suggested that several innate pathways are activated during SFV replication. Strong type I IFN responses are induced by SFV vectors, and they can act as adjuvant to coadministered protein on Ab production (84,85). We have also recently shown that the stimulatory effects by the SFV vectors on the innate immune system act in part through the dsRNA receptors TLR3 and Mda5 (86,87).…”

Section: Discussionmentioning

confidence: 99%

Comparative Prime-Boost Vaccinations Using Semliki Forest Virus, Adenovirus, and ALVAC Vectors Demonstrate Differences in the Generation of a Protective Central Memory CTL Response against the P815 Tumor

Näslund

Uyttenhove

Nordström

et al. 2007

The Journal of Immunology

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Tumor-specific Ags are potential target molecules in the therapeutic treatment of cancer. One way to elicit potent immune responses against these Ags is to use recombinant viruses, which activate both the innate and the adaptive arms of the immune system. In this study, we have compared Semliki Forest virus (SFV), adenovirus, and ALVAC (poxvirus) vectors for their capacity to induce CD8+ T cell responses against the P1A tumor Ag and to elicit protection against subsequent challenge injection of P1A-expressing P815 tumor cells in DBA/2 mice. Both homologous and heterologous prime-boost regimens were studied. In most cases, both higher CD8+ T cell responses and better tumor protections were observed in mice immunized with heterologous prime-boost regimens, suggesting that the combination of different viral vectors is beneficial for the induction of an effective immune response. However, homologous immunization with SFV provided potent tumor protection despite a rather moderate primary CD8+ T cell response as compared with mice immunized with recombinant adenovirus. SFV-immunized mice showed a rapid and more extensive expansion of P1A-specific CD8+ T cells in the tumor-draining lymph node after tumor challenge and had a higher frequency of CD62L+ P1A-specific T cells in the blood, spleen, and lymph nodes as compared with adenoimmunized mice. Our results indicate that not only the magnitude but in particular the quality of the CD8+ T cell response correlates with tumor protection.

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“…IFN-␣␤ bioassay was performed as described (37). IFN-␣, IFN-␤, and IL-12p40 or IL-12p70 ELISAs were performed using commercial kits distributed by PBL Laboratories and R&D Systems, respectively.…”

Section: Cytokine Titrationsmentioning

confidence: 99%

DAP12 Signaling Regulates Plasmacytoid Dendritic Cell Homeostasis and Down-Modulates Their Function during Viral Infection

Sjölin

Robbins

Bessou

et al. 2006

The Journal of Immunology

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DAP12 is an ITAM-containing adaptor molecule conveying activating properties to surface receptors on many cell types. We show here that DAP12 paradoxically down-modulates plasmacytoid dendritic cell (pDC) cytokine production in vivo during murine CMV (MCMV) infection. Higher levels of IFN-αβ and IL-12 were detected upon MCMV infection or CpG treatment in DAP12-deficient (DAP12°) mice as compared with wild-type (WT) mice. This resulted from altered homeostasis and enhanced responsiveness of pDCs in DAP12° animals. Increased numbers of pDCs were observed in the periphery of both naive and MCMV-infected DAP12° mice. A higher proportion of pDCs was activated in infected DAP12° mice, as demonstrated by intracellular staining using an optimized protocol for simultaneous detection of IFN-α and IFN-β. The homeostasis of WT and DAP12° pDCs did not differ in mixed bone marrow chimeric mice. In addition, a similar efficiency of pDC differentiation was observed in vitro in Fms-like tyrosine kinase receptor 3 ligand cultures of WT and DAP12° bone marrow cells. This suggests that DAP12 signaling effects on pDC homeostasis are indirect. In contrast, in response to CpG, DAP12-mediated effects on both IL-12 and IFN-αβ production were intrinsic to the pDCs. However, in response to MCMV, only IL-12 but not IFN-αβ production was affected by pDC-intrinsic DAP12 signaling. Thus, DAP12 signaling in pDCs can mediate different regulatory effects on their functions, depending on the mechanisms of pDC activation. The potential implications of the regulation of pDC functions by DAP12 for promoting health over disease are discussed.

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Early Alpha/Beta Interferon Production by Myeloid Dendritic Cells in Response to UV-Inactivated Virus Requires Viral Entry and Interferon Regulatory Factor 3 but Not MyD88

Cited by 58 publications

References 78 publications

Prime-Boost Immunization Strategies against Chikungunya Virus

Prime-Boost Immunization Strategies against Chikungunya Virus

Comparative Prime-Boost Vaccinations Using Semliki Forest Virus, Adenovirus, and ALVAC Vectors Demonstrate Differences in the Generation of a Protective Central Memory CTL Response against the P815 Tumor

DAP12 Signaling Regulates Plasmacytoid Dendritic Cell Homeostasis and Down-Modulates Their Function during Viral Infection

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