A virus-encoded type I interferon decoy receptor enables evasion of host immunity through cell-surface binding

Nature Communications, Journal Year: 2018, Volume and Issue: 9(1)

Published: Dec. 17, 2018

Soluble cytokine decoy receptors are potent immune modulatory reagents with therapeutic applications. Some virus-encoded secreted interact glycosaminoglycans expressed at the cell surface, but biological significance of this activity in vivo is poorly understood. Here, we show type I interferon binding protein (IFNα/βBP) encoded by vaccinia and ectromelia viruses requires to confer full virulence these retain immunomodulatory activity. Expression a variant form IFNα/βBP that inhibits IFN activity, does not surface glycosaminoglycans, results highly attenuated similar deletion mutant viruses. Transcriptomics analysis infection receptor-deficient mice confirmed control main function vivo. We propose retention may largely enhance their

Language: Английский

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T‐cells producing multiple combinations of IFNγ, TNF and IL10 are associated with mild forms of dengue infection

Immunology, Journal Year: 2020, Volume and Issue: 160(1), P. 90 - 102

Published: March 4, 2020

Summary Multifunctional interleukin 10 (IL10) + Th1 cells have been implicated in favorable evolution of many infectious diseases, promoting an efficacious immune response while limiting immunopathology. Here, we investigated the presence multifunctional CD4 and CD8 T‐cells that expressed interferon gamma (IFNγ), IL10 tumor necrosis factor (TNF), or its combinations during dengue infection. Peripheral blood mononuclear (PBMCs) from outpatients with (mild forms) hospitalized patients (or warning signs severe dengue) were cultured envelope (ENV) NS3 peptide libraries DENV critical (hospitalization period) convalescence phases. The production IFNγ, TNF by was assessed flow cytometry. Our data show mild dengue, when compared presented higher frequencies like NS3‐specific IFNγ/IL10‐producing phase NS3‐ ENV‐specific producing IFNγ/IL10. In addition, high levels IFNγ/TNF IFNγ/TNF/IL10 also observed group. We produced cytokines as measured intracellular content single producer T‐cells. Importantly, simultaneously displayed positive correlation platelet levels, suggesting a protective role this population. Tc1 associated presentation, these play clinical

Language: Английский

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Virus-encoded cytokine and chemokine decoy receptors

Current Opinion in Immunology, Journal Year: 2020, Volume and Issue: 66, P. 50 - 56

Published: May 8, 2020

Language: Английский

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Targeting ectromelia virus and TNF/NF-κB or STAT3 signaling for effective treatment of viral pneumonia

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(8)

Published: Feb. 17, 2022

Significance Antivirals are ineffective in treating viral pneumonia if administered after 48 h post onset of disease symptoms. Lung pathology during respiratory infections is triggered by the host inflammatory response and tissue damage caused replicating virus. Therefore, targeting both virus inflammation would be more effective pneumonia. Simultaneous treatment with an anti-inflammatory drug TNF or STAT3 combined antiviral significantly improved clinical disease, reduced lung load protected mice from severe ectromelia infection. The suppressed multiple proinflammatory cytokines cytokine-signaling pathways, including NF-κB STAT3. Late symptoms, alone cannot ameliorate pneumonia, as it reduce effectively.

Language: Английский

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Cell surface nucleocapsid protein expression: A betacoronavirus immunomodulatory strategy

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(28)

Published: July 3, 2023

We recently reported that SARS-CoV-2 nucleocapsid (N) protein is abundantly expressed on the surface of both infected and neighboring uninfected cells, where it enables activation Fc receptor-bearing immune cells with anti-N antibodies (Abs) inhibits leukocyte chemotaxis by binding chemokines (CHKs). Here, we extend these findings to N from common cold human coronavirus (HCoV)-OC43, which also robustly noninfected heparan sulfate/heparin (HS/H). HCoV-OC43 binds high affinity same set 11 CHKs as N, but a nonoverlapping six cytokines. As CXCL12β-mediated migration in assays, do all highly pathogenic HCoV proteins. Together, our indicate cell plays important evolutionarily conserved roles manipulating host innate immunity target for adaptive immunity.

Language: Английский

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TNF controls a speed-accuracy tradeoff in the cell death decision to restrict viral spread

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: May 20, 2021

Rapid death of infected cells is an important antiviral strategy. However, fast decisions that are based on limited evidence can be erroneous and cause unnecessary cell subsequent tissue damage. How optimize their decision making strategy to maximize both speed accuracy unclear. Here, we show exposure TNF, which secreted by macrophages during viral infection, causes change from "slow accurate" "fast error-prone". Mathematical modeling combined with experiments in culture whole organ the regulation critical prevent HSV-1 spread. These findings demonstrate immune cellular cognitive processes dynamically changes a tissues' tolerance for self-damage, required protect against

Language: Английский

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TNF Decoy Receptors Encoded by Poxviruses

Pathogens, Journal Year: 2021, Volume and Issue: 10(8), P. 1065 - 1065

Published: Aug. 22, 2021

Tumour necrosis factor (TNF) is an inflammatory cytokine produced in response to viral infections that promotes the recruitment and activation of leukocytes sites infection. This TNF-based host essential limit virus spreading, thus poxviruses have evolutionarily adopted diverse molecular mechanisms counteract TNF antiviral action. These include expression poxvirus-encoded soluble receptors or proteins able bind neutralize other members ligand superfamily, acting as decoy receptors. article reviews detail various identified date genomes from different poxvirus species, with a special focus on their impact pathogenesis potential use therapeutic molecules.

Language: Английский

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Poxvirus-encoded TNF receptor homolog dampens inflammation and protects from uncontrolled lung pathology during respiratory infection

Proceedings of the National Academy of Sciences, Journal Year: 2020, Volume and Issue: 117(43), P. 26885 - 26894

Published: Oct. 12, 2020

Significance Viruses have coevolved with their hosts and developed strategies to dampen, evade, or subvert the host immune response provide an advantage virus. We show that ectromelia virus (ECTV) encodes a TNF receptor (TNFR) homolog, which provides by dampening levels inflammation. Infection of ECTV-resistant mice mutant lacking viral TNFR (vTNFR) caused significant lung pathology death due secretion excessive other inflammatory cytokines. In vitro, recombinant vTNFR from ECTV orthopoxviruses bound membrane-associated down-regulated gene expression through reverse signaling. benefits enabling survival, potentially facilitating spread, should

Language: Английский

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Insights into ligand binding by a viral tumor necrosis factor (TNF) decoy receptor yield a selective soluble human type 2 TNF receptor

Journal of Biological Chemistry, Journal Year: 2019, Volume and Issue: 294(13), P. 5214 - 5227

Published: Feb. 5, 2019

Etanercept is a soluble form of the tumor necrosis factor receptor 2 (TNFR2) that inhibits pathological (TNF) responses in rheumatoid arthritis and other inflammatory diseases. However, besides TNF, etanercept also blocks lymphotoxin-α (LTα), which has no clear therapeutic value might aggravate some adverse effects associated with etanercept. Poxviruses encode TNFR2 homologs, termed viral TNF decoy receptors (vTNFRs), display unique specificity properties. For instance, cytokine response modifier D (CrmD) mouse human LTα, but it inactive against LTα. Here, we analyzed molecular basis these immunomodulatory activities ectromelia virus–encoded CrmD. We found overall mechanism to bind LTα from origin fairly conserved CrmD dominated by groove under its 50s loop. ligand-specific binding determinants optimize for inhibition ligands, especially TNF. Moreover, show inability inhibit caused Glu-Phe-Glu motif 90s Importantly, transfer this diminished anti-LTα activity >60-fold while weakening TNF-inhibitory capacity 3-fold. This new variant could potentially be used clinic as safer alternative conventional work most detailed study vTNFR–ligand interactions date illustrates better knowledge vTNFRs can provide valuable information improve current anti-TNF therapies. Harnessing poxviral know-how anti-cytokine therapiesJournal Biological ChemistryVol. 294Issue 13PreviewPoxviruses have evolved efficient proteins mammalian cytokines chemokines suppress host immunity. Here Pontejo et al. examine detail how one such protein, CrmD, both chemokines, interacts targets. They apply their findings refine increase specificity, providing an elegant example benefits mining therapeutically useful information. Full-Text PDF Open Access

Language: Английский

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Mutation of FMDV Lpro H138 residue drives viral attenuation in cell culture and in vivo in swine

Frontiers in Veterinary Science, Journal Year: 2022, Volume and Issue: 9

Published: Oct. 31, 2022

The foot-and-mouth disease virus (FMDV) leader proteinase (Lpro) is a papain like protease that cleaves the viral polyprotein and several host factors affecting cell translation induction of innate immunity. Introduction Lpro mutations ablating catalytic activity not tolerated by virus, however, complete coding sequence deletion or introduction targeted amino acid substitutions can render viable progeny. In proof-of-concept studies, we have previously identified characterized FMDV mutants are attenuated in culture animals, while retaining their capacity for inducing strong adaptive By using molecular modeling, now His residue (H138), resides outside substrate binding domain, highly conserved across serotypes. Mutation H138 renders possible variants reduced virulence vitro vivo. Kinetics studies showed A12-LH138L mutant replicates similarly to A12-wild type (WT) cells do offer immune selective pressure, but attenuation observed upon infection primary low passage porcine epithelial cells. Western blot analysis on protein extracts from these cells, revealed processing initiation factor eIF-4G was slightly delayed, no degradation sensors effector molecules such as NF-κB G3BP2 observed, higher levels interferon (IFN) IFN-stimulated genes (ISGs) were induced after with compared WT FMDV. Consistent results inoculation swine this resulted mild, some cases, clinical serological response. These further support previous evidence reliable target derive numerous strains alone combination could be exploited development novel FMD vaccine platforms.

Language: Английский

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