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Plasmacytoid dendritic cells control dengue and Chikungunya virus infections via IRF7-regulated interferon responses.

ABSTRACT: Type I interferon (IFN-I) responses are critical for the control of RNA virus infections, however, many viruses, including Dengue (DENV) and Chikungunya (CHIKV) virus, do not directly activate plasmacytoid dendritic cells (pDCs), robust IFN-I producing cells. Herein, we demonstrated that DENV and CHIKV infected cells are sensed by pDCs, indirectly, resulting in selective IRF7 activation and IFN-I production, in the absence of other inflammatory cytokine responses. To elucidate pDC immunomodulatory functions, we developed a mouse model in which IRF7 signaling is restricted to pDC. Despite undetectable levels of IFN-I protein, pDC-restricted IRF7 signaling controlled both viruses and was sufficient to protect mice from lethal CHIKV infection. Early pDC IRF7-signaling resulted in amplification of downstream antiviral responses, including an accelerated natural killer (NK) cell-mediated type II IFN response. These studies revealed the dominant, yet indirect role of pDC IRF7-signaling in directing both type I and II IFN responses during arbovirus infections.

SUBMITTER: Webster B

PROVIDER: S-EPMC6008049 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Plasmacytoid dendritic cells control dengue and Chikungunya virus infections via IRF7-regulated interferon responses.

Webster Brian B Werneke Scott W SW Zafirova Biljana B This Sébastien S Coléon Séverin S Décembre Elodie E Paidassi Helena H Bouvier Isabelle I Joubert Pierre-Emmanuel PE Duffy Darragh D Walzer Thierry T Albert Matthew L ML Dreux Marlène M

eLife 20180619

Type I interferon (IFN-I) responses are critical for the control of RNA virus infections, however, many viruses, including Dengue (DENV) and Chikungunya (CHIKV) virus, do not directly activate plasmacytoid dendritic cells (pDCs), robust IFN-I producing cells. Herein, we demonstrated that DENV and CHIKV infected cells are sensed by pDCs, indirectly, resulting in selective IRF7 activation and IFN-I production, in the absence of other inflammatory cytokine responses. To elucidate pDC immunomodulato ...[more]

PMID: 29914621

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Project description:BACKGROUND:Atopy and viral respiratory tract infections synergistically promote asthma exacerbations. IgE cross-linking inhibits critical virus-induced IFN-? responses of plasmacytoid dendritic cells (pDCs), which can be deficient in patients with allergic asthma. OBJECTIVE:We sought to determine whether reducing IgE levels in vivo with omalizumab treatment increases pDC antiviral IFN-? responses in inner-city children with asthma. METHODS:PBMCs and pDCs isolated from children with exacerbation-prone asthma before and during omalizumab treatment were stimulated ex vivo with rhinovirus and influenza in the presence or absence of IgE cross-linking. IFN-? levels were measured in supernatants, and mRNA expression of IFN-? pathway genes was determined by using quantitative RT-PCR (qRT-PCR) in cell pellets. Fc?RI? protein levels and mRNA expression were measured in unstimulated cells by using flow cytometry and qRT-PCR, respectively. Changes in these outcomes and associations with clinical outcomes were analyzed, and statistical modeling was used to identify risk factors for asthma exacerbations. RESULTS:Omalizumab treatment increased rhinovirus- and influenza-induced PBMC and rhinovirus-induced pDC IFN-? responses in the presence of IgE cross-linking and reduced pDC surface Fc?RI? expression. Omalizumab-induced reductions in pDC Fc?RI? levels were significantly associated with a lower asthma exacerbation rate during the outcome period and correlated with increases in PBMC IFN-? responses. PBMC Fc?RI? mRNA expression measured on study entry significantly improved an existing model of exacerbation prediction. CONCLUSIONS:These findings indicate that omalizumab treatment augments pDC IFN-? responses and attenuates pDC Fc?RI? protein expression and provide evidence that these effects are related. These results support a potential mechanism underlying clinical observations that allergic sensitization is associated with increased susceptibility to virus-induced asthma exacerbations.

Dataset Information

Plasmacytoid dendritic cells control dengue and Chikungunya virus infections via IRF7-regulated interferon responses.

Publications

Plasmacytoid dendritic cells control dengue and Chikungunya virus infections via IRF7-regulated interferon responses.

Similar Datasets

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