Multi‐layered stochasticity and paracrine signal propagation shape the type‐I interferon response

Rand, Ulfert; Rinas, Melanie; Schwerk, Johannes; Nöhren, Gesa; Linnes, Melanie; Kröger, Andrea; Floßdorf, Michael; Kály‐Kullai, Kristóf; Hauser, Hansjörg; Höfer, Thomas; Köster, Mario

doi:10.1038/msb.2012.17

Cited by 143 publications

(265 citation statements)

References 46 publications

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“…This finding supports earlier observations that vigorous IFN synthesis by a small number of cells in an infected organ may confer an astonishingly high degree of antiviral protection (28,29). Our results clearly demonstrate that virus-infected epithelial cells and macrophages are able to mediate antiviral protection via type I IFN and presumably other cytokines, unless this process is actively blocked by virusencoded IFN-antagonistic factors.…”

Section: Cd11csupporting

confidence: 80%

Visualizing the Beta Interferon Response in Mice during Infection with Influenza A Viruses Expressing or Lacking Nonstructural Protein 1

Kallfass

Lienenklaus

Staeheli

2013

J Virol

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bThe innate host defense against influenza virus is largely dependent on the type I interferon (IFN) system. However, surprisingly little is known about the cellular source of IFN in the infected lung. To clarify this question, we employed a reporter mouse that contains the firefly luciferase gene in place of the IFN-␤-coding region. IFN-␤-producing cells were identified either by simultaneous immunostaining of lungs for luciferase and cellular markers or by generating conditional reporter mice that express luciferase exclusively in defined cell types. Two different strains of influenza A virus were employed that either do or do not code for nonstructural protein 1 (NS1), which strongly suppresses innate immune responses of infected cells. We found that epithelial cells and lung macrophages, which represent the prime host cells for influenza viruses, showed vigorous IFN-␤ responses which, however, were severely reduced and delayed if the infecting virus was able to produce NS1. Interestingly, CD11c؉ cell populations that were either expressing or lacking macrophage markers produced the bulk of IFN-␤ at 48 h after infection with wildtype influenza A virus. Our results demonstrate that the virus-encoded IFN-antagonistic factor NS1 disarms specifically epithelial cells and lung macrophages, which otherwise would serve as main mediators of the early response against infection by influenza virus.

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Section: Cd11csupporting

confidence: 80%

Visualizing the Beta Interferon Response in Mice during Infection with Influenza A Viruses Expressing or Lacking Nonstructural Protein 1

Kallfass

Lienenklaus

Staeheli

2013

J Virol

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“…Only a fraction (e.g., 20-30%) of the monocyte population stained positive for IRF5 and IRF3 nuclear accumulation after TLR8 or TLR4 activation, respectively. This fits with a stochastic model of IFN-b production in a cell population, which is explained by variations in limiting components at the cellular level (39,40). TLR8 is also a potent inducer of IL-12 in human monocytes (28,31), whereas IRF5 regulates macrophage polarization and drives IL-12 and IL-23 production and Th1-Th17 activation (41).…”

Section: Discussionmentioning

confidence: 99%

TLR8 Senses Staphylococcus aureus RNA in Human Primary Monocytes and Macrophages and Induces IFN-β Production via a TAK1–IKKβ–IRF5 Signaling Pathway

Bergstrøm

Aune

Awuh

et al. 2015

The Journal of Immunology

124

162

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Staphylococcus aureus may cause serious infections and is one of the most lethal and common causes of sepsis. TLR2 has been described as the main pattern recognition receptor that senses S. aureus and elicits production of proinflammatory cytokines via MyD88–NF-κB signaling. S. aureus can also induce the production of IFN-β, a cytokine that requires IFN regulatory factors (IRFs) for its transcription, but the signaling mechanism for IFN-β induction by S. aureus are unclear. Surprisingly, we demonstrate that activation of TLR2 by lipoproteins does not contribute to IFN-β production but instead can suppress the induction of IFN-β in human primary monocytes and monocyte-derived macrophages. The production of IFN-β was induced by TLR8-mediated sensing of S. aureus RNA, which triggered IRF5 nuclear accumulation, and this could be antagonized by concomitant TLR2 signaling. The TLR8-mediated activation of IRF5 was dependent on TAK1 and IκB kinase (IKK)β, which thus reveals a physiological role of the recently described IRF5-activating function of IKKβ. TLR8–IRF5 signaling was necessary for induction of IFN-β and IL-12 by S. aureus, and it also contributed to the induction of TNF. In conclusion, our study demonstrates a physiological role of TLR8 in the sensing of entire S. aureus in human primary phagocytes, including the induction of IFN-β and IL-12 production via a TAK1–IKKβ–IRF5 pathway that can be inhibited by TLR2 signaling.

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“…However, there is considerable variability in the ability of cells to upregulate IFN genes and to respond to these cytokines (36,37). This implies that the complex scenario of the type I IFN reaction to virus infection also needs to be studied at the level of single cells to fully understand the dynamic forces within a given cell population.…”

Section: Discussionmentioning

confidence: 99%

“…4B). Possible reasons include the possibility that other, lesswell-characterized viral factors, such as the PA-X protein, compromise the cell's capacity to upregulate ISGs (53) or simply that not all cells are able to respond to virus-induced IFN secretion due to stochastic events (37). The observation that only about 30% of the infected cells in NDV-infected culture showed an ISG signature is compatible with the latter explanation, but further experiments will be required to confirm this.…”

Section: Discussionmentioning

confidence: 99%

“…One important challenge that needs to be considered to overcome this limitation is the considerable variation among cells in their capability to respond to biological stimuli (33), which also includes IFN and ISG expression. In fact, only a fraction of cells stimulated with a RIG-I ligand upregulate IFN gene transcription due to stochastic events (34)(35)(36), and cells within one culture differ widely in the minimal type I IFN concentration required to upregulate ISGs (37). This suggests that it is important to determine the activation and execution of the antiviral IFN response at the level of single cells.…”

mentioning

confidence: 99%

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Fluorescence-Activated Cell Sorting-Based Analysis Reveals an Asymmetric Induction of Interferon-Stimulated Genes in Response to Seasonal Influenza A Virus

Recum-Knepper

Sadewasser

Weinheimer

et al. 2015

J Virol

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Influenza A virus (IAV) infection provokes an antiviral response involving the expression of type I and III interferons (IFN) and Influenza A viruses (IAVs) are prototypic members of the Orthomyxoviridae family, featuring a segmented RNA genome composed of eight single-stranded RNAs that have negative polarity (1). IAVs circulate in the human population, causing periodic epidemic outbreaks and occasional pandemic waves of respiratory disease (2). Moreover, there is a large natural IAV host reservoir in wild aquatic birds, such as ducks and geese, in which the viruses cause mainly mild or no apparent symptoms. IAV strains are usually well adapted to their particular host species, which is reflected not only in the existence of stable virus lineages but also in polymorphic amino acid positions in viral proteins distinctively found in human or avian strains (3).IAVs target the epithelial cell layers lining the human respiratory tract, in which they are subject to immune control in infected cells, mediated by the antiviral type I interferon (IFN) response (4). Many of the key events and factors driving the IFN response have been identified and involve initial recognition of the viral genomic 5=-triphosphorylated RNA by the intracellular RNA helicase RIG-I, which governs a signaling module culminating in the activation of transcription factors, such as IRF-3 and NF-B, thereby inducing the transcription of type I IFN genes (5, 6). Type I IFNs comprise 14 subtypes of IFN-␣ and one IFN-␤ that are secreted from virus-infected cells and exert antiviral effects against many virus families, including IAV (4, 7). Type I IFNs secreted by

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Multi‐layered stochasticity and paracrine signal propagation shape the type‐I interferon response

Abstract: Live-cell imaging and mathematical modelling of the type-I interferon response to viral infection reveal that multiple layers of the cellular response are stochastic events in individual cells, while paracrine propagation of the IFN signal results in reliable antiviral protection.

Cited by 143 publications

References 46 publications

Visualizing the Beta Interferon Response in Mice during Infection with Influenza A Viruses Expressing or Lacking Nonstructural Protein 1

Visualizing the Beta Interferon Response in Mice during Infection with Influenza A Viruses Expressing or Lacking Nonstructural Protein 1

TLR8 Senses Staphylococcus aureus RNA in Human Primary Monocytes and Macrophages and Induces IFN-β Production via a TAK1–IKKβ–IRF5 Signaling Pathway

Fluorescence-Activated Cell Sorting-Based Analysis Reveals an Asymmetric Induction of Interferon-Stimulated Genes in Response to Seasonal Influenza A Virus

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