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Viruses
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The Inflammasomes - Key Players in Antiviral Response
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The Inflammasomes - Key Players in Antiviral Response

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Viral Immunology, Vaccines, and Antivirals".

Deadline for manuscript submissions: 30 November 2024 | Viewed by 16502

Special Issue Editors

Prof. Dr. Dong-Yan Jin

grade E-Mail Website
Guest Editor
School of Biomedical Sciences, The University of Hong Kong, Pokfulam 999077, Hong Kong, China
Interests: molecular virology and oncology
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Tsan Sam Xiao

E-Mail Website
Guest Editor
Department of Pathology, Case Western Reserve University, Cleveland, OH, USA
Interests: inflammasome signaling pathways and pyroptosis

Special Issue Information

Dear Colleagues,

The inflammasomes are oligomeric signaling platforms that activate the proteolytic activity of caspases such as caspase-1, which trigger the maturation and secretion of cytokines, including IL-1β and IL-18. The inflammatory caspases also cleave the pore-forming protein gasdermin D that assembles membrane pores to initiate a proinflammatory form of cell death termed pyroptosis. Multiple inflammasomes such as NLRP3 and AIM2 have been implicated in innate antiviral immunity. However, the role of inflammasomes in host protection may be dependent on complex virus–host interactions, and excessive inflammation may contribute to severe tissue damage that exacerbates pathogenesis. This Special Issue of Viruses welcomes both primary research articles and comprehensive reviews that shed light on the complex roles of inflammasomes in antiviral responses. Topics of special interest may include viral modulators of inflammasome activation and pyroptosis; roles of inflammasomes and pyroptosis in viral replication, infection, and pathogenesis; mechanism of proinflammatory cytokine storm; as well as implications of inflammasomes in the design and development of antivirals and vaccines.

Prof. Dr. Dong-Yan Jin
Prof. Dr. Tsan Sam Xiao
Guest Editors

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Keywords

  • inflammasome
  • cytokine
  • pyroptosis
  • infection
  • virus-host interactions
  • viral pathogenesis

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Published Papers (7 papers)

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Research

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12 pages, 2316 KiB  
Article
SARS-CoV-2 ORF3a-Mediated NF-κB Activation Is Not Dependent on TRAF-Binding Sequence
by Brianna M. Busscher, Henock B. Befekadu, Zhonghua Liu and Tsan Sam Xiao
Viruses 2023, 15(11), 2229; https://doi.org/10.3390/v15112229 - 8 Nov 2023
Cited by 1 | Viewed by 1655
Abstract
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused a global pandemic of Coronavirus Disease 2019 (COVID-19). Excessive inflammation is a hallmark of severe COVID-19, and several proteins encoded in the SARS-CoV-2 genome are capable of stimulating inflammatory pathways. Among these, the accessory [...] Read more.
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused a global pandemic of Coronavirus Disease 2019 (COVID-19). Excessive inflammation is a hallmark of severe COVID-19, and several proteins encoded in the SARS-CoV-2 genome are capable of stimulating inflammatory pathways. Among these, the accessory protein open reading frame 3a (ORF3a) has been implicated in COVID-19 pathology. Here we investigated the roles of ORF3a in binding to TNF receptor-associated factor (TRAF) proteins and inducing nuclear factor kappa B (NF-κB) activation. X-ray crystallography and a fluorescence polarization assay revealed low-affinity binding between an ORF3a N-terminal peptide and TRAFs, and a dual-luciferase assay demonstrated NF-κB activation by ORF3a. Nonetheless, mutation of the N-terminal TRAF-binding sequence PIQAS in ORF3a did not significantly diminish NF-κB activation in our assay. Our results thus suggest that the SARS-CoV-2 protein may activate NF-κB through alternative mechanisms. Full article
(This article belongs to the Special Issue The Inflammasomes - Key Players in Antiviral Response)
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13 pages, 4752 KiB  
Article
ZBP1 Drives IAV-Induced NLRP3 Inflammasome Activation and Lytic Cell Death, PANoptosis, Independent of the Necroptosis Executioner MLKL
by R. K. Subbarao Malireddi, Bhesh Raj Sharma, Ratnakar R. Bynigeri, Yaqiu Wang, Jianlin Lu and Thirumala-Devi Kanneganti
Viruses 2023, 15(11), 2141; https://doi.org/10.3390/v15112141 - 24 Oct 2023
Cited by 7 | Viewed by 2973
Abstract
Influenza A virus (IAV) continues to pose a significant global health threat, causing severe respiratory infections that result in substantial annual morbidity and mortality. Recent research highlights the pivotal role of innate immunity, cell death, and inflammation in exacerbating the severity of respiratory [...] Read more.
Influenza A virus (IAV) continues to pose a significant global health threat, causing severe respiratory infections that result in substantial annual morbidity and mortality. Recent research highlights the pivotal role of innate immunity, cell death, and inflammation in exacerbating the severity of respiratory viral diseases. One key molecule in this process is ZBP1, a well-recognized innate immune sensor for IAV infection. Upon activation, ZBP1 triggers the formation of a PANoptosome complex containing ASC, caspase-8, and RIPK3, among other molecules, leading to inflammatory cell death, PANoptosis, and NLRP3 inflammasome activation for the maturation of IL-1β and IL-18. However, the role for other molecules in this process requires further evaluation. In this study, we investigated the role of MLKL in regulating IAV-induced cell death and NLRP3 inflammasome activation. Our data indicate IAV induced inflammatory cell death through the ZBP1-PANoptosome, where caspases and RIPKs serve as core components. However, IAV-induced lytic cell death was only partially dependent on RIPK3 at later timepoints and was fully independent of MLKL throughout all timepoints tested. Additionally, NLRP3 inflammasome activation was unaffected in MLKL-deficient cells, establishing that MLKL and MLKL-dependent necroptosis do not act upstream of NLRP3 inflammasome activation, IL-1β maturation, and lytic cell death during IAV infection. Full article
(This article belongs to the Special Issue The Inflammasomes - Key Players in Antiviral Response)
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14 pages, 3013 KiB  
Article
NLRP3 Inflammasome Involved with Viral Replication in Cytopathic NADL BVDV Infection and IFI16 Inflammasome Connected with IL-1β Release in Non-Cytopathic NY-1 BVDV Infection in Bovine Macrophages
by Claudia Gallegos-Rodarte, Omar Escobar-Chavarría, Meztli Miroslava Cantera-Bravo, Rosa Elena Sarmiento-Silva and Alejandro Benitez-Guzman
Viruses 2023, 15(7), 1494; https://doi.org/10.3390/v15071494 - 30 Jun 2023
Cited by 1 | Viewed by 1826
Abstract
Inflammasomes are multiprotein complexes that play a role in the processing of proinflammatory cytokines such as interleukin 1 beta (IL-1β). The secretion of IL-1β in bovine macrophages infected with the bovine viral diarrhea virus (BVDV) cytopathic strain NADL (NADLcp-BVDV) is caspase 1-dependent. In [...] Read more.
Inflammasomes are multiprotein complexes that play a role in the processing of proinflammatory cytokines such as interleukin 1 beta (IL-1β). The secretion of IL-1β in bovine macrophages infected with the bovine viral diarrhea virus (BVDV) cytopathic strain NADL (NADLcp-BVDV) is caspase 1-dependent. In the present study, we found that in macrophages infected with NADL, the NLRP3 inflammasome participated in the maturation of IL-1β as the level decreased from 4629.3 pg/mL to 897.0 pg/mL after treatment with cytokine release inhibitory drug 3 (CRID3). Furthermore, NLRP3 activation has implications regarding viral replication, as there was a decrease in the viral titer until 1 log of a supernatant of macrophages that were inhibited with CRID3 remained. In the case of the non-cytopathic BVDV strain NY-1 (NY-1 ncpBVDV), IL-1β secretion is not affected by NLRP3, but could be related to the IFI16 inflammasome; we found a colocalization of IFI16 with ASC using confocal microscopy in infected macrophages with the NY-1 ncp-BVDV biotype. To relate IFI16 activation to IL-1β release, we used ODN TTAGGG (A151), a competitive inhibitor of IFI16; the results show a decrease in its level from 248 pg/mL to 128.3 pg/mL. Additionally, we evaluated the caspase 1 activation downstream of IFI16 and found a decrease in the IL-1β from 252.9 pg/mL to 63.5 pg/mL when caspase 1 was inhibited with Y-VAD. Our results provide an improved understanding of the mechanisms involved in the viral replication, inflammation and pathogenesis of bovine viral diarrhea. Full article
(This article belongs to the Special Issue The Inflammasomes - Key Players in Antiviral Response)
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Review

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18 pages, 1306 KiB  
Review
Investigating the Nexus of NLRP3 Inflammasomes and COVID-19 Pathogenesis: Unraveling Molecular Triggers and Therapeutic Strategies
by Qun He, Da Hu, Fuqiang Zheng, Wenxuan Chen, Kanghong Hu, Jinbiao Liu, Chenguang Yao, Hanluo Li and Yanhong Wei
Viruses 2024, 16(2), 213; https://doi.org/10.3390/v16020213 - 31 Jan 2024
Cited by 1 | Viewed by 1802
Abstract
The coronavirus disease 2019 (COVID-19) global pandemic, caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), has been marked by severe cases demonstrating a “cytokine storm”, an upsurge of pro-inflammatory cytokines in the bloodstream. NLRP3 inflammasomes, integral to the innate immune system, [...] Read more.
The coronavirus disease 2019 (COVID-19) global pandemic, caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), has been marked by severe cases demonstrating a “cytokine storm”, an upsurge of pro-inflammatory cytokines in the bloodstream. NLRP3 inflammasomes, integral to the innate immune system, are speculated to be activated by SARS-CoV-2 within host cells. This review investigates the potential correlation between NLRP3 inflammasomes and COVID-19, exploring the cellular and molecular mechanisms through which SARS-CoV-2 triggers their activation. Furthermore, promising strategies targeting NLRP3 inflammasomes are proposed to mitigate the excessive inflammatory response provoked by SARS-CoV-2 infection. By synthesizing existing studies, this paper offers insights into NLRP3 as a therapeutic target, elucidating the interplay between COVID-19 and its pathophysiology. It serves as a valuable reference for future clinical approaches in addressing COVID-19 by targeting NLRP3, thus providing potential avenues for therapeutic intervention. Full article
(This article belongs to the Special Issue The Inflammasomes - Key Players in Antiviral Response)
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20 pages, 1510 KiB  
Review
Targeting Inflammasome Activation in Viral Infection: A Therapeutic Solution?
by Chuan-Han Deng, Tian-Qi Li, Wei Zhang, Qi Zhao and Ying Wang
Viruses 2023, 15(7), 1451; https://doi.org/10.3390/v15071451 - 27 Jun 2023
Cited by 11 | Viewed by 3042
Abstract
Inflammasome activation is exclusively involved in sensing activation of innate immunity and inflammatory response during viral infection. Accumulating evidence suggests that the manipulation of inflammasome assembly or its interaction with viral proteins are critical factors in viral pathogenesis. Results from pilot clinical trials [...] Read more.
Inflammasome activation is exclusively involved in sensing activation of innate immunity and inflammatory response during viral infection. Accumulating evidence suggests that the manipulation of inflammasome assembly or its interaction with viral proteins are critical factors in viral pathogenesis. Results from pilot clinical trials show encouraging results of NLRP3 inflammasome suppression in reducing mortality and morbidity in SARS-CoV-2-infected patients. In this article, we summarize the up-to-date understanding of inflammasomes, including NLRP3, AIM2, NLRP1, NLRP6, and NLRC4 in various viral infections, with particular focus on RNA viruses such as SARS-CoV-2, HIV, IAV, and Zika virus and DNA viruses such as herpes simplex virus 1. We also discuss the current achievement of the mechanisms involved in viral infection-induced inflammatory response, host defense, and possible therapeutic solutions. Full article
(This article belongs to the Special Issue The Inflammasomes - Key Players in Antiviral Response)
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17 pages, 778 KiB  
Review
Roles and Mechanisms of NLRP3 in Influenza Viral Infection
by Junling Niu and Guangxun Meng
Viruses 2023, 15(6), 1339; https://doi.org/10.3390/v15061339 - 8 Jun 2023
Cited by 5 | Viewed by 2478
Abstract
Pathogenic viral infection represents a major challenge to human health. Due to the vast mucosal surface of respiratory tract exposed to the environment, host defense against influenza viruses has perpetually been a considerable challenge. Inflammasomes serve as vital components of the host innate [...] Read more.
Pathogenic viral infection represents a major challenge to human health. Due to the vast mucosal surface of respiratory tract exposed to the environment, host defense against influenza viruses has perpetually been a considerable challenge. Inflammasomes serve as vital components of the host innate immune system and play a crucial role in responding to viral infections. To cope with influenza viral infection, the host employs inflammasomes and symbiotic microbiota to confer effective protection at the mucosal surface in the lungs. This review article aims to summarize the current findings on the function of NACHT, LRR and PYD domains-containing protein 3 (NLRP3) in host response to influenza viral infection involving various mechanisms including the gut–lung crosstalk. Full article
(This article belongs to the Special Issue The Inflammasomes - Key Players in Antiviral Response)
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Other

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12 pages, 2859 KiB  
Case Report
Inflammasome-Driven Fatal Acute-on-Chronic Liver Failure Triggered by Mild COVID-19
by Vivian Chih-Wei Chen, Craig Ryan Joseph, Wharton O. Y. Chan, Wan Rong Sia, Qi Su, Xin Xiu Sam, Hemavathi Tamilarasan, Yun Yan Mah, Wei Lun Ng, Joe Yeong, Lin-Fa Wang, Thinesh L. Krishnamoorthy, Wei-Qiang Leow, Matae Ahn and Wan Cheng Chow
Viruses 2024, 16(10), 1646; https://doi.org/10.3390/v16101646 - 21 Oct 2024
Viewed by 1365
Abstract
Inflammasome is linked to many inflammatory diseases, including COVID-19 and autoimmune liver diseases. While severe COVID-19 was reported to exacerbate liver failure, we report a fatal acute-on-chronic liver failure (ACLF) in a stable primary biliary cholangitis-autoimmune hepatitis overlap syndrome patient triggered by a [...] Read more.
Inflammasome is linked to many inflammatory diseases, including COVID-19 and autoimmune liver diseases. While severe COVID-19 was reported to exacerbate liver failure, we report a fatal acute-on-chronic liver failure (ACLF) in a stable primary biliary cholangitis-autoimmune hepatitis overlap syndrome patient triggered by a mild COVID-19 infection. Postmortem liver biopsy showed sparse SARS-CoV-2-infected macrophages with extensive ASC (apoptosis-associated speck-like protein containing a CARD) speck-positive hepatocytes, correlating with elevated circulating ASC specks and inflammatory cytokines, and depleted blood monocyte subsets, indicating widespread liver inflammasome activation. This first report of a fatal inflammatory cascade in an autoimmune liver disease triggered by a mild remote viral infection hopes to elucidate a less-described pathophysiology of ACLF that could prompt consideration of new diagnostic and therapeutic options. Full article
(This article belongs to the Special Issue The Inflammasomes - Key Players in Antiviral Response)
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