Interleukin-1β Signaling in Dendritic Cells Induces Antiviral Interferon Responses

ABSTRACT Induction of interferon beta (IFN-β), IFN-stimulated genes (ISGs), and inflammatory responses is critical for control of viral infection. We recently identified an essential linkage of stimulation of the inflammatory cytokine interleukin-1β (IL-1β) and induction of ISGs that function as hos...

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Autores principales:	Lauren D. Aarreberg, Courtney Wilkins, Hilario J. Ramos, Richard Green, Michael A. Davis, Kwan Chow, Michael Gale
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	IL-1 West Nile virus flavivirus genomics inflammasome innate immunity Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/751d065760ac4db8a1549d19660af4f5
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spelling	oai:doaj.org-article:751d065760ac4db8a1549d19660af4f52021-11-15T15:53:26ZInterleukin-1β Signaling in Dendritic Cells Induces Antiviral Interferon Responses10.1128/mBio.00342-182150-7511https://doaj.org/article/751d065760ac4db8a1549d19660af4f52018-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00342-18https://doaj.org/toc/2150-7511ABSTRACT Induction of interferon beta (IFN-β), IFN-stimulated genes (ISGs), and inflammatory responses is critical for control of viral infection. We recently identified an essential linkage of stimulation of the inflammatory cytokine interleukin-1β (IL-1β) and induction of ISGs that function as host restriction pathways against the emerging flavivirus West Nile virus (WNV) in vivo. Here we utilized ex vivo global transcriptome analysis of primary dendritic cells, known targets of WNV replication, to define gene signatures required for this IL-1β-driven antiviral response. Dendritic cells that were deficient in IL-1 receptor signaling showed dysregulation of cell-intrinsic defense genes and loss of viral control during WNV infection. Surprisingly, we found that in wild-type cells, IL-1β treatment, in the absence of infection, drove the transcription of IFN-β and ISGs at late times following treatment. Expression of these antiviral innate immune genes was dependent on the transcription factor IFN regulatory factor 3 (IRF3) and appears to reflect a general shift in IL-1β signaling from an early inflammatory response to a late IFN-mediated response. These data demonstrate that inflammatory and antiviral signals integrate to control viral infection in myeloid cells through a process of IL-1β-to-IRF3 signaling crosstalk. Strategies to exploit these cytokines in the activation of host defense programs should be investigated as novel therapeutic approaches against individual pathogens. IMPORTANCE West Nile virus is an emerging mosquito-borne flavivirus that can result in serious illness, neuropathology, and death in infected individuals. Currently, there are no vaccines or therapies for human use against West Nile virus. Immune control of West Nile virus infection requires inflammatory and antiviral responses, though the effect that each arm of this response has on the other is unclear. The significance of our research is in defining how virus-induced inflammatory responses regulate critical antiviral immune programs for effective control of West Nile virus infection. These data identify essential mechanisms of immune control that can inform therapeutic efforts against West Nile virus, with potential efficacy against other neuroinvasive viruses.Lauren D. AarrebergCourtney WilkinsHilario J. RamosRichard GreenMichael A. DavisKwan ChowMichael GaleAmerican Society for MicrobiologyarticleIL-1West Nile virusflavivirusgenomicsinflammasomeinnate immunityMicrobiologyQR1-502ENmBio, Vol 9, Iss 2 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	IL-1 West Nile virus flavivirus genomics inflammasome innate immunity Microbiology QR1-502
spellingShingle	IL-1 West Nile virus flavivirus genomics inflammasome innate immunity Microbiology QR1-502 Lauren D. Aarreberg Courtney Wilkins Hilario J. Ramos Richard Green Michael A. Davis Kwan Chow Michael Gale Interleukin-1β Signaling in Dendritic Cells Induces Antiviral Interferon Responses
description	ABSTRACT Induction of interferon beta (IFN-β), IFN-stimulated genes (ISGs), and inflammatory responses is critical for control of viral infection. We recently identified an essential linkage of stimulation of the inflammatory cytokine interleukin-1β (IL-1β) and induction of ISGs that function as host restriction pathways against the emerging flavivirus West Nile virus (WNV) in vivo. Here we utilized ex vivo global transcriptome analysis of primary dendritic cells, known targets of WNV replication, to define gene signatures required for this IL-1β-driven antiviral response. Dendritic cells that were deficient in IL-1 receptor signaling showed dysregulation of cell-intrinsic defense genes and loss of viral control during WNV infection. Surprisingly, we found that in wild-type cells, IL-1β treatment, in the absence of infection, drove the transcription of IFN-β and ISGs at late times following treatment. Expression of these antiviral innate immune genes was dependent on the transcription factor IFN regulatory factor 3 (IRF3) and appears to reflect a general shift in IL-1β signaling from an early inflammatory response to a late IFN-mediated response. These data demonstrate that inflammatory and antiviral signals integrate to control viral infection in myeloid cells through a process of IL-1β-to-IRF3 signaling crosstalk. Strategies to exploit these cytokines in the activation of host defense programs should be investigated as novel therapeutic approaches against individual pathogens. IMPORTANCE West Nile virus is an emerging mosquito-borne flavivirus that can result in serious illness, neuropathology, and death in infected individuals. Currently, there are no vaccines or therapies for human use against West Nile virus. Immune control of West Nile virus infection requires inflammatory and antiviral responses, though the effect that each arm of this response has on the other is unclear. The significance of our research is in defining how virus-induced inflammatory responses regulate critical antiviral immune programs for effective control of West Nile virus infection. These data identify essential mechanisms of immune control that can inform therapeutic efforts against West Nile virus, with potential efficacy against other neuroinvasive viruses.
format	article
author	Lauren D. Aarreberg Courtney Wilkins Hilario J. Ramos Richard Green Michael A. Davis Kwan Chow Michael Gale
author_facet	Lauren D. Aarreberg Courtney Wilkins Hilario J. Ramos Richard Green Michael A. Davis Kwan Chow Michael Gale
author_sort	Lauren D. Aarreberg
title	Interleukin-1β Signaling in Dendritic Cells Induces Antiviral Interferon Responses
title_short	Interleukin-1β Signaling in Dendritic Cells Induces Antiviral Interferon Responses
title_full	Interleukin-1β Signaling in Dendritic Cells Induces Antiviral Interferon Responses
title_fullStr	Interleukin-1β Signaling in Dendritic Cells Induces Antiviral Interferon Responses
title_full_unstemmed	Interleukin-1β Signaling in Dendritic Cells Induces Antiviral Interferon Responses
title_sort	interleukin-1β signaling in dendritic cells induces antiviral interferon responses
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/751d065760ac4db8a1549d19660af4f5
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Interleukin-1β Signaling in Dendritic Cells Induces Antiviral Interferon Responses

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