A Positive Feedback Amplifier Circuit That Regulates Interferon (IFN)-Stimulated Gene Expression and Controls Type I and Type II IFN Responses

Michalska, Agata; Błaszczyk, Katarzyna; Wesoły, Joanna; Bluyssen, Hans A.R.

doi:10.3389/fimmu.2018.01135

Cited by 253 publications

(277 citation statements)

References 124 publications

(202 reference statements)

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“…S7B; S7A-D; Methods). In accord with our data, the presence of positive feedback has been previously described for IFN signaling (Michalska et al, 2018). It is important to note that positive feedback in the IFN response involves not only RNase L-sensitive mediators (IFN/ISG mRNAs), but also RNase L-resistant activators (accumulation of IFN proteins and phosphorylation of the transcription factor STAT) ( Fig.…”

Section: Decay and Synthesis Kinetics Protect Ifn Mrnas From 2-5amdsupporting

confidence: 92%

Concerted 2-5A-Mediated mRNA Decay and Transcription Reprogram Protein Synthesis in dsRNA Response

Rath

Prangley

Donovan

et al. 2018

Preprint

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RNA degradation by RNase L during 2-5A-mediated decay (2-5AMD) is a conserved mammalian stress response to viral and endogenous double-stranded RNA (dsRNA). 2-5AMD onsets rapidly and facilitates a switch of protein synthesis from homeostasis to production of interferons (IFNs). To understand the mechanism of this protein synthesis reprogramming, we examined 2-5AMD in human cells. 2-5AMD triggers polysome collapse characteristic of a translation initiation defect, but translation initiation complexes and ribosomes purified from the translation-arrested cells remain functional. Using spike-in RNA-seq we found that basal messenger RNAs (mRNAs) rapidly decay, while mRNAs encoding IFNs and IFN-stimulated genes evade 2-5AMD and accumulate. The IFN evasion results from the combined effect of better mRNA stability and positive feedback amplification in the IFN response. Therefore, 2-5AMD and transcription act in concert to revamp the cellular mRNA composition. The resulting preferential accumulation of innate immune mRNAs establishes "prioritized" synthesis of defense proteins.

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Section: Decay and Synthesis Kinetics Protect Ifn Mrnas From 2-5amdsupporting

confidence: 92%

Concerted 2-5A-Mediated mRNA Decay and Transcription Reprogram Protein Synthesis in dsRNA Response

Rath

Prangley

Donovan

et al. 2018

Preprint

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“…In individual P1, almost all cell types demonstrated higher expression of IRF7 compared to pre-infection and 1-year timepoints (Fig. S3C), highlighting the pervasiveness of IFN-I in response to high levels of viremia and potentially indicative of the positive feedback loop it induces 54–56 . Since plasmacytoid DCs (pDCs) are known to produce IFN- α and IFN- β in response to HIV 57 , we also assayed single pDCs at peak viremia and 1-year post-infection using a plate-based scRNA-Seq method compatible with enrichment by FACS (Smart-Seq2 58 ) (Fig.…”

Section: Resultsmentioning

confidence: 96%

Integrated Single-Cell Analysis of Multicellular Immune Dynamics during Hyper-Acute HIV-1 Infection

Kazer

Aicher

Muema

et al. 2019

Preprint

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30Cellular immunity is critical for controlling intracellular pathogens, but the dynamics and 31 cooperativity of the evolving host response to infection are not well defined. Here, we apply single-32 cell RNA-sequencing to longitudinally profile pre-and immediately post-HIV infection peripheral 33 immune responses of multiple cell types in four untreated individuals. Onset of viremia induces a 34 strong transcriptional interferon response integrated across most cell types, with subsequent pro-35 inflammatory T cell differentiation, monocyte MHC-II upregulation, and cytolytic killing. With 36 longitudinal sampling, we nominate key intra-and extracellular drivers that induce these 37 programs, and assign their multi-cellular targets, temporal ordering, and duration in acute 38 infection. Two individuals studied developed spontaneous viral control, associated with initial 39 elevated frequencies of proliferating cytotoxic cells, inclusive of a previously unappreciated 40 proliferating natural killer (NK) cell subset. Our study presents a unified framework for 41 characterizing immune evolution during a persistent human viral infection at single-cell resolution, 42 and highlights programs that may drive response coordination and influence clinical trajectory. 43 44 54Recently, high-throughput single-cell RNA-sequencing (scRNA-Seq) has emerged as a 55 powerful tool to characterize, transcriptome-wide, complex human systems in health and disease 56 at single-cell resolution [3][4][5][6][7][8][9] . When applied to a collection of samples across a disease setting, this 57 approach provides a platform for investigating cell types, states, interactions, and drivers 58 associated with that disease; this information can be used to develop testable hypotheses on 59 therapeutic modulations that may ameliorate disease state 7,8 . Meanwhile, within an individual, 60longitudinal sampling provides an opportunity to decipher, at unprecedented resolution and 61 absent potentially confounding inter-individual variability 7 , shifts in these same variables, and to 62 3 associate observed changes with internal or external perturbations 10-12 . Such sampling of a host's 63 exposure to a pathogen could provide foundational insights into essential cellular response 64 features and their coordination, empowering the rational design of improved prophylactic 65 interventions. 66Illustratively, a better understanding of the interplay between innate and adaptive immune 67 responses at the very earliest stages of a viral infection, and its impact on long-term disease, 68 could reveal principles to accelerate prevention efforts. Human Immunodeficiency Virus (HIV) has 69 been the subject of thorough study, and thus is a well-considered model system for examining 70 host responses to a pathogen. Moreover, although the development of antiretroviral therapy 71 (ART) 13 , as well as implementation of pre-exposure prophylaxis (PrEP) 14 and combination 72 prevention efforts, has improved the lives of persons living with HIV, increased life expectancie...

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“…The type I IFN response includes a positive feedback loop whereby secreted IFN upregulates pattern recognition receptors, such as RIG-I and transcription factors such as IRF7, to amplify the response (51). It was therefore of interest to test the hypothesis that MLAV VP40, MARV VP40 and EBOV VP24 inhibit virus-induced induction of the IFN response as a result of their inhibition of IFN-induced positive feedback loop.…”

Section: Resultsmentioning

confidence: 99%

“…However, the mechanism(s) for these inhibitory activities are incompletely defined, although EBOV VP24 was implicated as having an effect post-IRF3 phosphorylation (34). Inhibition of STAT1 activation and IFN-induced gene expression would be expected to impair the positive feedback loop in which IFN-α/β induces expression of IFN stimulated genes, including RIG-I and IRF7, to amplify IFN response (51). This prompted additional experiments to determine whether the detected inhibition was a product of blocking the positive feedback loop through VP40 inhibition of Jak-STAT signaling or an additional mechanism acting on the production side.…”

Section: Discussionmentioning

confidence: 99%

Impact of Měnglà virus proteins on human and bat innate immune pathways

Williams

Gibbons

Keiffer

et al. 2019

Preprint

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AbstractMěnglà virus (MLAV), identified in Rousettus bats, is a phylogenetically distinct member of the family Filoviridae. Because filoviruses Ebola virus (EBOV) and Marburg virus (MARV) modulate host innate immune pathways, MLAV VP35, VP40 and VP24 proteins were compared with their EBOV and MARV homologs for innate immune pathway modulation. In human and Rousettus cells, MLAV VP35 behaved like EBOV and MARV VP35s, inhibiting virus-induced activation of the interferon (IFN)-β promoter. MLAV VP35 inhibited IRF3 phosphorylation and interacted with PACT, a host protein engaged by EBOV VP35 to inhibit RIG-I signaling. MLAV VP35 also inhibited PKR activation. MLAV VP40 was demonstrated to inhibit type I IFN induced gene expression in human and bat cells. It blocked STAT1 tyrosine phosphorylation induced either by type I IFN or over-expressed Jak1, paralleling MARV VP40. MLAV VP40 also inhibited virus-induced IFNβ promoter activation, a property shared by MARV VP40 and EBOV VP24. The inhibition of IFN induction was preserved in the presence of a Jak kinase inhibitor, demonstrating that inhibition of Jak-STAT signaling is not sufficient to explain inhibition of IFNβ promoter activation. MLAV VP24 did not inhibit IFN-induced gene expression or bind karyopherin α5, properties of EBOV VP24. MLAV VP24 also differed from MARV VP24 in that it failed to interact with Keap1 or activate an antioxidant response element reporter gene, due to the absence of a Keap1-binding motif. These studies demonstrate similarities between MLAV and MARV in how they suppress IFN responses and differences in how MLAV VP24 interacts with host pathways.ImportanceEBOV and MARV, members of the family Filoviridae, are highly pathogenic zoonotic viruses that cause severe disease in humans. Both viruses use several mechanisms to modulate the host innate immune response, and these likely contribute to severity of disease. Here, we demonstrate that MLAV, a filovirus newly discovered in a bat, suppresses antiviral type I interferon responses in both human and bat cells. Inhibitory activities are possessed by MLAV VP35 and VP40, which parallels how MARV blocks IFN responses. However, whereas MARV activates cellular antioxidant responses through an interaction between its VP24 protein and host protein Keap1, MLAV VP24 lacks a Keap1 binding motif and fails to activate this cytoprotective response. These data indicate that MLAV possesses immune suppressing functions that could facilitate human infection. They also demonstrate key differences in MLAV versus either EBOV or MARV engagement of host signaling pathways.

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A Positive Feedback Amplifier Circuit That Regulates Interferon (IFN)-Stimulated Gene Expression and Controls Type I and Type II IFN Responses

Cited by 253 publications

References 124 publications

Concerted 2-5A-Mediated mRNA Decay and Transcription Reprogram Protein Synthesis in dsRNA Response

Concerted 2-5A-Mediated mRNA Decay and Transcription Reprogram Protein Synthesis in dsRNA Response

Integrated Single-Cell Analysis of Multicellular Immune Dynamics during Hyper-Acute HIV-1 Infection

Impact of Měnglà virus proteins on human and bat innate immune pathways

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