The Induction of IL-1β Secretion Through the NLRP3 Inflammasome During Ebola Virus Infection

Halfmann, Peter; Hill-Batorski, Lindsay; Kawaoka, Yoshihiro

doi:10.1093/infdis/jiy433

Cited by 26 publications

(23 citation statements)

References 18 publications

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“…This inflammatory response was accompanied by an equally rapid and potent IL-10 response and somewhat lower levels of IL-12, IL-18, and IFN-α2. These data -in a highly relevant ex vivo system -corroborate previous observations from human cell lines and in vitro-generated monocyte-derived DCs and macrophages (11,14,16,18). The relatively low levels of NK cell-and T cell-activating cytokines together with the abundance of IL-10 suggest the generation of a tightly regulated cytokine environment within hours of exposure Figure 5.…”

Section: Discussionsupporting

confidence: 86%

“…Impairment of the type I IFN response is accompanied by an excessive proinflammatory cytokine response (2,13). In vitro studies have shown that the Ebola virus GP is a potent ligand for TLR-4 and induces activation of noninfected monocytic cell lines and monocyte-derived DCs and macrophages to produce cytokines (14)(15)(16)(17)(18). Importantly, an initial type I IFN response accompanied by modest and transient IL-1β and TNF-α secretion correlated with survival among EVD patients, whereas high IL-10 was associated with fatal outcome (13,19,20).…”

Section: Resultsmentioning

confidence: 99%

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Ebola virus glycoprotein stimulates IL-18–dependent natural killer cell responses

Wagstaffe

Clutterbuck

Bockstal

et al. 2020

Journal of Clinical Investigation

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BACKGROUND. NK cells are activated by innate cytokines and viral ligands to kill virus-infected cells. These functions are enhanced during secondary immune responses and after vaccination by synergy with effector T cells and virus-specific antibodies. In human Ebola virus infection, clinical outcome is strongly associated with the initial innate cytokine response, but the role of NK cells has not been thoroughly examined. METHODS.The novel 2-dose heterologous Adenovirus type 26.ZEBOV (Ad26.ZEBOV) and modified vaccinia Ankara-BN-Filo (MVA-BN-Filo) vaccine regimen is safe and provides specific immunity against Ebola glycoprotein, and is currently in phase 2 and 3 studies. Here, we analyzed NK cell phenotype and function in response to Ad26.ZEBOV, MVA-BN-Filo vaccination regimen and in response to in vitro Ebola glycoprotein stimulation of PBMCs isolated before and after vaccination. RESULTS.We show enhanced NK cell proliferation and activation after vaccination compared with baseline. Ebola glycoprotein-induced activation of NK cells was dependent on accessory cells and TLR-4-dependent innate cytokine secretion (predominantly from CD14 + monocytes) and enriched within less differentiated NK cell subsets. Optimal NK cell responses were dependent on IL-18 and IL-12, whereas IFN-γ secretion was restricted by high concentrations of IL-10. CONCLUSION.This study demonstrates the induction of NK cell effector functions early after Ad26.ZEBOV, MVA-BN-Filo vaccination and provides a mechanism for the activation and regulation of NK cells by Ebola glycoprotein. TRIAL REGISTRATION. ClinicalTrials.gov NCT02313077.

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Section: Discussionsupporting

confidence: 86%

Section: Resultsmentioning

confidence: 99%

Ebola virus glycoprotein stimulates IL-18–dependent natural killer cell responses

Wagstaffe

Clutterbuck

Bockstal

et al. 2020

Journal of Clinical Investigation

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“…NLRP3 is an innate immune signaling receptor. Once activated, it initiates caspase1-mediated proteolytic activation of the IL-1β family of cytokines, and induces an inflammatory response [23][24][25]. The expression of these innate immune Fig.…”

Section: Discussionmentioning

confidence: 99%

Simple hypertrophic tonsils have more active innate immune and inflammatory responses than hypertrophic tonsils with recurrent inflammation in children

Qun

et al. 2020

Journal of Otolaryngology - Head & Neck Surgery

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Background: Tonsil hypertrophy has negative impact on children's health, but its pathogenesis remains obscure despite the fact that numerous bacteriological studies have been carried out. Understanding the innate immune and inflammatory states of hypertrophic tonsils with different clinical manifestations is of great significance for defining the pathogenesis of tonsil hypertrophy and establishing treatment strategies. The present study was undertaken to examine the characteristics of innate immunity and inflammation in children with hypertrophic palatine tonsils and different clinical manifestations. Methods: Tonsil tissues were surgically removed from the patients and classified based on the patients' clinical manifestations. The patients were divided into three groups: 1) Control group; 2) Tonsil Hypertrophy (TH) group; and 3) Tonsil Hypertrophy combined with Recurrent Infection (TH + RI) group. The immune and inflammatory statuses of these tissues were characterized using qRT-PCR and ELISA methods. Results: Viral protein 1 (VP1) was highly expressed in TH group, but not in TH + RI group. In TH group, elevated expression was observed in the innate immune mediators, including retinoic acid-inducible gene I (RIG-I), interferon alpha (IFN-α), mitochondrial antiviral-signaling protein (MAVS), NLR family pyrin domain containing 3 (NLRP3), tolllike receptor (TLR) 4 and TLR7. Consistent with the innate immune profile, the expression of inflammatory markers (IL-1β, NF-κB and IL-7) was also significantly elevated in TH group. Meanwhile, the COX-2/PGE2/EP4 signaling pathway was found to be involved in the inflammatory response and the formation of fibroblasts. Conclusions: Innate immune and inflammatory responses are more active in simple hypertrophic tonsils, rather than hypertrophic tonsils with recurrent inflammation. A local relative immune deficiency in the hypertrophic tonsils may be a causative factor for recurrent tonsillitis in TH + RI. These differences, together with the patient's clinical manifestations, suggest that tonsillar hypertrophy might be regulated by diverse immune and/or inflammatory mechanism through which novel therapeutic strategies might be created.

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“…Several studies also show that NLRP3 is also a sensor for viral infection. NLRP3 inflammasome signalling drives IL‐1β production in Ebola infection 84 . However, some viruses, such as Sendai virus and NS1 mutant influenza A virus, inhibit IL‐1β production by preventing NLRP3 assembly and detection of these viruses, highlighting the limitations of NLRP3 in combating such viral infections 85,86 .…”

Section: Inflammasomes: Key Mediators Of Inflammatory Diseasesmentioning

confidence: 99%

The complex interplay between endoplasmic reticulum stress and the NLRP3 inflammasome: a potential therapeutic target for inflammatory disorders

et al. 2021

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Inflammation is the result of a complex network of cellular and molecular interactions and mechanisms that facilitate immune protection against intrinsic and extrinsic stimuli, particularly pathogens, to maintain homeostasis and promote tissue healing. However, dysregulation in the immune system elicits excess/abnormal inflammation resulting in unintended tissue damage and causes major inflammatory diseases including asthma, chronic obstructive pulmonary disease, atherosclerosis, inflammatory bowel diseases, sarcoidosis and rheumatoid arthritis. It is now widely accepted that both endoplasmic reticulum (ER) stress and inflammasomes play critical roles in activating inflammatory signalling cascades. Notably, evidence is mounting for the involvement of ER stress in exacerbating inflammasome‐induced inflammatory cascades, which may provide a new axis for therapeutic targeting in a range of inflammatory disorders. Here, we comprehensively review the roles, mechanisms and interactions of both ER stress and inflammasomes, as well as their interconnected relationships in inflammatory signalling cascades. We also discuss novel therapeutic strategies that are being developed to treat ER stress‐ and inflammasome‐related inflammatory disorders.

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The Induction of IL-1β Secretion Through the NLRP3 Inflammasome During Ebola Virus Infection

Cited by 26 publications

References 18 publications

Ebola virus glycoprotein stimulates IL-18–dependent natural killer cell responses

Ebola virus glycoprotein stimulates IL-18–dependent natural killer cell responses

Simple hypertrophic tonsils have more active innate immune and inflammatory responses than hypertrophic tonsils with recurrent inflammation in children

The complex interplay between endoplasmic reticulum stress and the NLRP3 inflammasome: a potential therapeutic target for inflammatory disorders

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