The SARS-CoV-2 papain-like protease suppresses type I interferon responses by deubiquitinating STING DOI Open Access
Dan Cao, Lian Duan, Bin Huang

et al.

Science Signaling, Journal Year: 2023, Volume and Issue: 16(783)

Published: May 2, 2023

The SARS-CoV-2 papain-like protease (PLpro), which has deubiquitinating activity, suppresses the type I interferon (IFN-I) antiviral response. We investigated mechanism by PLpro antagonizes cellular responses. In HEK392T cells, removed K63-linked polyubiquitin chains from Lys 289 of stimulator genes (STING). PLpro-mediated deubiquitination STING disrupted STING-IKKε-IRF3 complex that induces production IFN-β and IFN-stimulated cytokines chemokines. human airway cells infected with SARS-CoV-2, combined treatment agonist diABZi inhibitor GRL0617 resulted in synergistic inhibition replication increased IFN-I PLpros seven coronaviruses (SARS-CoV-2, SARS-CoV, MERS-CoV, HCoV-229E, HCoV-HKU1, HCoV-OC43, HCoV-NL63) four variants concern (α, β, γ, δ) all bound to suppressed STING-stimulated responses HEK293T cells. These findings reveal how inhibits signaling through a general used coronaviral dysregulate facilitate viral innate immune evasion. also identified simultaneous pharmacological activation as potentially effective strategy for therapy against SARS-CoV-2.

Language: Английский

Innate immunity: the first line of defense against SARS-CoV-2 DOI Open Access
Michael Diamond, Thirumala‐Devi Kanneganti

Nature Immunology, Journal Year: 2022, Volume and Issue: 23(2), P. 165 - 176

Published: Feb. 1, 2022

Language: Английский

Citations

503
Cellular functions of cGAS-STING signaling DOI
Chen Chen, Pinglong Xu

Trends in Cell Biology, Journal Year: 2022, Volume and Issue: 33(8), P. 630 - 648

Published: Nov. 24, 2022

Language: Английский

Citations

204
ZBP1-dependent inflammatory cell death, PANoptosis, and cytokine storm disrupt IFN therapeutic efficacy during coronavirus infection DOI Creative Commons
Rajendra Karki, SangJoon Lee, Raghvendra Mall

et al.

Science Immunology, Journal Year: 2022, Volume and Issue: 7(74)

Published: May 19, 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for disease 2019 (COVID-19), continues to cause substantial morbidity and mortality in ongoing global pandemic. Understanding fundamental mechanisms that govern innate immune inflammatory responses during SARS-CoV-2 infection is critical developing effective therapeutic strategies. Whereas interferon (IFN)–based therapies are generally expected be beneficial viral infection, clinical trials COVID-19 have shown limited efficacy potential detrimental effects of IFN treatment infection. However, underlying this failure remain unknown. In study, we found induced Z-DNA-binding protein 1 (ZBP1)–mediated cell death, PANoptosis, human murine macrophages lungs mice infected with β-coronaviruses, including mouse hepatitis (MHV). patients COVID-19, expression sensor ZBP1 was increased cells from those who succumbed compared recovered, further suggesting a link between pathology. mice, IFN-β after β-coronavirus lethality, genetic deletion Zbp1 or its Zα domain suppressed death protected IFN-mediated lethality Overall, our results identify limits therapy by driving lethality. Therefore, inhibiting activity may improve therapy, paving way development new critically needed therapeutics as well other infections conditions where pathology occur.

Language: Английский

Citations

182
Role of the cGAS–STING pathway in systemic and organ-specific diseases DOI Open Access
Sladjana Skopelja‐Gardner, Jie An, Keith B. Elkon

et al.

Nature Reviews Nephrology, Journal Year: 2022, Volume and Issue: 18(9), P. 558 - 572

Published: June 22, 2022

Language: Английский

Citations

170
Immune dysregulation and immunopathology induced by SARS-CoV-2 and related coronaviruses — are we our own worst enemy? DOI Creative Commons
Lok-Yin Roy Wong, Stanley Perlman

Nature reviews. Immunology, Journal Year: 2021, Volume and Issue: 22(1), P. 47 - 56

Published: Nov. 26, 2021

Human coronaviruses cause a wide spectrum of disease, ranging from mild common colds to acute respiratory distress syndrome and death. Three highly pathogenic human — severe coronavirus (SARS-CoV), Middle East SARS-CoV-2 have illustrated the epidemic pandemic potential coronaviruses, better understanding their disease-causing mechanisms is urgently needed for rational design therapeutics. Analyses patients revealed marked dysregulation immune system in cases infection, there ample evidence that aberrant responses are typified by impaired induction interferons, exuberant inflammatory delayed adaptive responses. In addition, various viral proteins been shown impair interferon signalling induce inflammasome activation. This suggests disease associated with mediated both dysregulated host active interference. Here we discuss our current involved each these scenarios. this Perspective, Lok-Yin Roy Wong Stanley Perlman consider how 2 (SARS-CoV-2) related able drive immunopathology. They provide an overview coronavirus-derived molecules interfere key innate responses, including pathways complement, NF-κB activation, as well activation immunity.

Language: Английский

Citations

164
The development of COVID-19 treatment DOI Creative Commons

Yongliang Yuan,

Baihai Jiao, Lili Qu

et al.

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Jan. 26, 2023

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a pandemic named disease 2019 (COVID-19) that has become the greatest worldwide public health threat this century. Recent studies have unraveled numerous mysteries SARS-CoV-2 pathogenesis and thus largely improved COVID-19 vaccines therapeutic strategies. However, important questions remain regarding its therapy. In review, recent research advances on mechanism are quickly summarized. We mainly discuss current therapy strategies for COVID-19, with an emphasis antiviral agents, neutralizing antibody therapies, Janus kinase inhibitors, steroids. When necessary, specific mechanisms history present, representative described in detail. Finally, we key outstanding future directions development treatment.

Language: Английский

Citations

164
Innate immunological pathways in COVID-19 pathogenesis DOI
Søren R. Paludan, Trine H. Mogensen

Science Immunology, Journal Year: 2022, Volume and Issue: 7(67)

Published: Jan. 7, 2022

Coronavirus disease 2019 (COVID-19) is a characterized by profound dysregulation of the innate immune system. This knowledge has emerged from large body single-cell omics studies patients with COVID-19, which have provided one most detailed cellular atlases human ever. However, we are only beginning to understand immunological pathways that govern host defense and immunopathology in COVID-19. In this review, discuss emerging understanding how SARS-CoV-2 host-derived molecules activate specific pattern recognition receptors elicit protective interferon responses pathological cytokine responses, particular focus on acute infection lung pathophysiology critical addition, these modulated virus-host interactions stress-sensing pathways. In-depth mechanisms will likely uncover molecular targets for treatment COVID-19 other viral infections. it reveal fine balance between beneficial versus causing responses.

Language: Английский

Citations

162
STING agonist diABZI induces PANoptosis and DNA mediated acute respiratory distress syndrome (ARDS) DOI Creative Commons

Yasmine Messaoud‐Nacer,

Elodie Culerier,

Stéphanie Rose

et al.

Cell Death and Disease, Journal Year: 2022, Volume and Issue: 13(3)

Published: March 25, 2022

Abstract Stimulator of interferon genes (STING) contributes to immune responses against tumors and may control viral infection including SARS-CoV-2 infection. However, activation the STING pathway by airway silica or smoke exposure leads cell death, self-dsDNA release, STING/type I IFN dependent acute lung inflammation/ARDS. The inflammatory response induced a synthetic non-nucleotide-based diABZI agonist, in comparison natural cyclic dinucleotide cGAMP, is unknown. A low dose (1 µg endotracheal route for 3 consecutive days) triggered an neutrophilic inflammation, disruption respiratory barrier, DNA release with NET formation, PANoptosis cytokines type inflammation. Downstream upregulation sensors cGAS, DDX41, IFI204, as well NLRP3 AIM2 inflammasomes, suggested secondary dsDNA danger signal. DNase treatment, inhibition formation together investigation gene-deficient mice highlighted extracellular TLR9, but not central diABZI-induced response. Therefore, death lead ARDS which be modeled diABZI. These results show that targeting activator therapeutic strategy enhance inflammation severe ARDS.

Language: Английский

Citations

150
A diamidobenzimidazole STING agonist protects against SARS-CoV-2 infection DOI Creative Commons
Fiachra Humphries, Liraz Shmuel-Galia, Zhaozhao Jiang

et al.

Science Immunology, Journal Year: 2021, Volume and Issue: 6(59)

Published: May 18, 2021

Pharmacological activation of STING protects against SARS-CoV-2 infection.

Language: Английский

Citations

135
Immune response in COVID-19: what is next? DOI Creative Commons
Qing Li, Ying Wang, Qiang Sun

et al.

Cell Death and Differentiation, Journal Year: 2022, Volume and Issue: 29(6), P. 1107 - 1122

Published: May 17, 2022

Abstract The coronavirus disease 2019 (COVID-19) has been a global pandemic for more than 2 years and it still impacts our daily lifestyle quality in unprecedented ways. A better understanding of immunity its regulation response to SARS-CoV-2 infection is urgently needed. Based on the current literature, we review here various virus mutations evolving manifestations along with alterations immune responses specific focuses innate response, neutrophil extracellular traps, humoral immunity, cellular immunity. Different types vaccines were compared analyzed based their unique properties elicit Various therapeutic strategies such as antibody, anti-viral medications inflammation control discussed. We predict that available continuously emerging new technologies, powerful administration schedules, effective public health measures, COVID-19 will be under near future.

Language: Английский

Citations

114