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2.
Inflamm Res ; 71(3): 293-307, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1729272

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is capable of inducing the activation of NACHT, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome, a macromolecular structure sensing the danger and amplifying the inflammatory response. The main product processed by NLRP3 inflammasome is interleukin (IL)-1ß, responsible for the downstream production of IL-6, which has been recognized as an important mediator in coronavirus disease 2019 (COVID-19). Since colchicine is an anti-inflammatory drug with the ability to block NLRP3 inflammasome oligomerization, this may prevent the release of active IL-1ß and block the detrimental effects of downstream cytokines, i.e. IL-6. To date, few randomized clinical trials and many observational studies with colchicine have been conducted, showing interesting signals. As colchicine is a nonspecific inhibitor of the NLRP3 inflammasome, compounds specifically blocking this molecule might provide increased advantages in reducing the inflammatory burden and its related clinical manifestations. This may occur through a selective blockade of different steps preceding NLRP3 inflammasome oligomerization as well as through a reduced release of the main cytokines (IL-1ß and IL-18). Since most evidence is based on observational studies, definitive conclusion cannot be drawn and additional studies are needed to confirm preliminary results and further dissect how colchicine and other NLRP3 inhibitors reduce the inflammatory burden and evaluate the timing and duration of treatment.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19/drug therapy , Colchicine/therapeutic use , Inflammasomes/immunology , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , SARS-CoV-2 , Animals , COVID-19/immunology , Humans
3.
Viruses ; 14(2)2022 01 31.
Article in English | MEDLINE | ID: covidwho-1715767

ABSTRACT

INTRODUCTION: This study investigated the spontaneous clinical course of patients with endomyocardial biopsy (EMB)-proven lymphocytic myocarditis and cardiac human herpesvirus 6 (HHV6) DNA presence, and the effectiveness of steroid-based intervention in HHV6-positive patients. RESULTS: 756 heart failure (HF) patients underwent an EMB procedure to determine the underlying cause of unexplained HF. Low levels of HHV6 DNA, detectable by nested PCR only, were found in 10.4% of the cases (n = 79) of which 62% (n = 49) showed myocardial inflammation. The spontaneous course of patients with EMB-proven HHV6 DNA-associated lymphocytic myocarditis (n = 26) showed significant improvements in the left ventricular ejection fraction (LVEF) and clinical symptoms, respectively, in 15/26 (60%) patients, 3-12 months after disease onset. EMB mRNA expression of components of the NLRP3 inflammasome pathway and protein analysis of cardiac remodeling markers, analyzed by real-time PCR and MALDI mass spectrometry, respectively, did not differ between HHV6-positive and -negative patients. In another cohort of patients with ongoing symptoms related to lymphocytic myocarditis associated with cardiac levels of HHV6-DNA copy numbers <500 copies/µg cardiac DNA, quantified by real-time PCR, the efficacy and safety of steroid-based immunosuppression for six months was investigated. Steroid-based immunosuppression improved the LVEF (≥5%) in 8/10 patients and reduced cardiac inflammation in 7/10 patients, without an increase in cardiac HHV6 DNA levels in follow-up EMBs. CONCLUSION: Low HHV6 DNA levels are frequently detected in the myocardium, independent of inflammation. In patients with lymphocytic myocarditis with low levels of HHV6 DNA, the spontaneous clinical improvement is nearby 60%. In selected symptomatic patients with cardiac HHV6 DNA copy numbers less than 500 copies/µg cardiac DNA and without signs of an active systemic HHV6 infection, steroid-based therapy was found to be effective and safe. This finding needs to be further confirmed in large, randomized trials.


Subject(s)
Herpesvirus 6, Human/physiology , Immunosuppressive Agents/administration & dosage , Myocarditis/drug therapy , Myocarditis/virology , Roseolovirus Infections/drug therapy , Roseolovirus Infections/virology , Steroids/administration & dosage , Adult , Aged , Biopsy , Cohort Studies , DNA, Viral/genetics , Female , Gene Dosage , Herpesvirus 6, Human/genetics , Herpesvirus 6, Human/isolation & purification , Humans , Male , Middle Aged , Myocarditis/immunology , Myocarditis/physiopathology , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , Roseolovirus Infections/immunology , Roseolovirus Infections/physiopathology , Stroke Volume
5.
EBioMedicine ; 75: 103803, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1587923

ABSTRACT

BACKGROUND: The Coronavirus Disease 2019 (COVID-19) pandemic has been a great threat to global public health since 2020. Although the advance on vaccine development has been largely achieved, a strategy to alleviate immune overactivation in severe COVID-19 patients is still needed. The NLRP3 inflammasome is activated upon SARS-CoV-2 infection and associated with COVID-19 severity. However, the processes by which the NLRP3 inflammasome is involved in COVID-19 disease remain unclear. METHODS: We infected THP-1 derived macrophages, NLRP3 knockout mice, and human ACE2 transgenic mice with live SARS-CoV-2 in Biosafety Level 3 (BSL-3) laboratory. We performed quantitative real-time PCR for targeted viral or host genes from SARS-CoV-2 infected mouse tissues, conducted histological or immunofluorescence analysis in SARS-CoV-2 infected mouse tissues. We also injected intranasally AAV-hACE2 or intraperitoneally NLRP3 inflammasome inhibitor MCC950 before SARS-CoV-2 infection in mice as indicated. FINDINGS: We have provided multiple lines of evidence that the NLRP3 inflammasome plays an important role in the host immune response to SARS-CoV-2 invasion of the lungs. Inhibition of the NLRP3 inflammasome attenuated the release of COVID-19 related pro-inflammatory cytokines in cell cultures and mice. The severe pathology induced by SARS-CoV-2 in lung tissues was reduced in Nlrp3-/- mice compared to wild-type C57BL/6 mice. Finally, specific inhibition of the NLRP3 inflammasome by MCC950 alleviated excessive lung inflammation and thus COVID-19 like pathology in human ACE2 transgenic mice. INTERPRETATION: Inflammatory activation induced by SARS-CoV-2 is an important stimulator of COVID-19 related immunopathology. Targeting the NLRP3 inflammasome is a promising immune intervention against severe COVID-19 disease. FUNDING: This work was supported by grants from the Bureau of Frontier Sciences and Education, CAS (grant no. QYZDJ-SSW-SMC005 to Y.G.Y.), the key project of the CAS "Light of West China" Program (to D.Y.) and Yunnan Province (202001AS070023 to D.Y.).


Subject(s)
COVID-19 , Lung , Macrophages , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , SARS-CoV-2/immunology , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/immunology , Animals , COVID-19/genetics , COVID-19/immunology , COVID-19/pathology , Disease Models, Animal , Humans , Lung/immunology , Lung/pathology , Lung/virology , Macrophages/immunology , Macrophages/pathology , Macrophages/virology , Male , Mice , Mice, Knockout , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , SARS-CoV-2/genetics , THP-1 Cells
6.
Viruses ; 13(10)2021 10 15.
Article in English | MEDLINE | ID: covidwho-1470996

ABSTRACT

Infections with viral pathogens are widespread and can cause a variety of different diseases. In-depth knowledge about viral triggers initiating an immune response is necessary to decipher viral pathogenesis. Inflammasomes, as part of the innate immune system, can be activated by viral pathogens. However, viral structural components responsible for inflammasome activation remain largely unknown. Here we analyzed glycoproteins derived from SARS-CoV-1/2, HCMV and HCV, required for viral entry and fusion, as potential triggers of NLRP3 inflammasome activation and pyroptosis in THP-1 macrophages. All tested glycoproteins were able to potently induce NLRP3 inflammasome activation, indicated by ASC-SPECK formation and secretion of cleaved IL-1ß. Lytic cell death via gasdermin D (GSDMD), pore formation, and pyroptosis are required for IL-1ß release. As a hallmark of pyroptosis, we were able to detect cleavage of GSDMD and, correspondingly, cell death in THP-1 macrophages. CRISPR-Cas9 knockout of NLRP3 and GSDMD in THP-1 macrophages confirmed and strongly support the evidence that viral glycoproteins can act as innate immunity triggers. With our study, we decipher key mechanisms of viral pathogenesis by showing that viral glycoproteins potently induce innate immune responses. These insights could be beneficial in vaccine development and provide new impulses for the investigation of vaccine-induced innate immunity.


Subject(s)
Immunity, Innate/immunology , Inflammasomes/immunology , Macrophages/immunology , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , Viral Envelope Proteins/immunology , Viral Fusion Proteins/immunology , Cell Line, Tumor , Cytomegalovirus/immunology , Hepacivirus/immunology , Humans , Interleukin-1beta/biosynthesis , Interleukin-1beta/immunology , Pyroptosis/immunology , SARS Virus/immunology , SARS-CoV-2/immunology , THP-1 Cells
7.
J Neuroimmunol ; 361: 577728, 2021 12 15.
Article in English | MEDLINE | ID: covidwho-1440213

ABSTRACT

We herein report, by using confocal immunofluorescence, the colocalization of the SARS-CoV-2 nucleocapsid within neurons, astrocytes, oligodendrocytes and microglia in three deceased COVID-19 cases, of between 78 and 85 years of age at death. The viral nucleocapsid was detected together with its ACE2 cell entry receptor, as well as the NLRP3 inflammasome in cerebral cortical tissues. It is noteworthy that NLRP3 was colocalized with CD68 + macrophages in the brain and lung of the deceased, suggesting the critical role of this type of inflammasome in SARS-CoV-2 lesions of the nervous system/lungs and supporting its potential role as a therapeutic target.


Subject(s)
Brain/virology , COVID-19/virology , Inflammasomes/immunology , Microglia/virology , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , SARS-CoV-2/pathogenicity , Aged , Aged, 80 and over , Astrocytes/virology , Autopsy , Brain/immunology , Brain/pathology , COVID-19/immunology , COVID-19/pathology , Female , Humans , Male , Microglia/immunology , Neurons/virology , Nucleocapsid , Oligodendroglia/virology
9.
J Leukoc Biol ; 111(3): 725-734, 2022 03.
Article in English | MEDLINE | ID: covidwho-1380391

ABSTRACT

Following on from the devastating spread of COVID-19, a major global priority has been the production, procurement, and distribution of effective vaccines to ensure that the global pandemic reaches an end. However, concerns were raised about worrying side effects, particularly the occurrence of thrombosis and thrombocytopenia after administration of the Oxford/AstraZeneca and Johnson & Johnson's Janssen COVID-19 vaccine, in a phenomenon being termed vaccine-induced thrombotic thrombocytopenia (VITT). Similar to heparin-induced thrombocytopenia (HIT), this condition has been associated with the development of anti-platelet factor 4 antibodies, purportedly leading to neutrophil-platelet aggregate formation. Although thrombosis has also been a common association with COVID-19, the precise molecular mechanisms governing its occurrence are yet to be established. Recently, increasing evidence highlights the NLRP3 (NOD-like, leucine-rich repeat domains, and pyrin domain-containing protein) inflammasome complex along with IL-1ß and effete neutrophils producing neutrophil extracellular traps (NETs) through NETosis. Herein, we propose and discuss that perhaps the incidence of VITT may be due to inflammatory reactions mediated via IL-1ß/NLRP3 inflammasome activation and consequent overproduction of NETs, where similar autoimmune mechanisms are observed in HIT. We also discuss avenues by which such modalities could be treated to prevent the occurrence of adverse events and ensure vaccine rollouts remain safe and on target to end the current pandemic.


Subject(s)
COVID-19 Vaccines/adverse effects , COVID-19/prevention & control , Extracellular Traps/immunology , Thrombocytopenia/etiology , Animals , COVID-19/immunology , COVID-19 Vaccines/therapeutic use , Humans , Inflammasomes/immunology , Interleukin-1beta/immunology , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , Thrombocytopenia/immunology , Thrombocytopenia/prevention & control , Thrombocytopenia/therapy
10.
EMBO J ; 40(18): e108249, 2021 09 15.
Article in English | MEDLINE | ID: covidwho-1323479

ABSTRACT

SARS-CoV-2 is an emerging coronavirus that causes dysfunctions in multiple human cells and tissues. Studies have looked at the entry of SARS-CoV-2 into host cells mediated by the viral spike protein and human receptor ACE2. However, less is known about the cellular immune responses triggered by SARS-CoV-2 viral proteins. Here, we show that the nucleocapsid of SARS-CoV-2 inhibits host pyroptosis by blocking Gasdermin D (GSDMD) cleavage. SARS-CoV-2-infected monocytes show enhanced cellular interleukin-1ß (IL-1ß) expression, but reduced IL-1ß secretion. While SARS-CoV-2 infection promotes activation of the NLRP3 inflammasome and caspase-1, GSDMD cleavage and pyroptosis are inhibited in infected human monocytes. SARS-CoV-2 nucleocapsid protein associates with GSDMD in cells and inhibits GSDMD cleavage in vitro and in vivo. The nucleocapsid binds the GSDMD linker region and hinders GSDMD processing by caspase-1. These insights into how SARS-CoV-2 antagonizes cellular inflammatory responses may open new avenues for treating COVID-19 in the future.


Subject(s)
COVID-19/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Nucleocapsid/metabolism , Phosphate-Binding Proteins/metabolism , Pyroptosis/physiology , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2/immunology , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Caspase 1/immunology , Caspase 1/metabolism , HEK293 Cells , Host-Pathogen Interactions , Humans , Inflammasomes/immunology , Inflammasomes/metabolism , Interleukin-1beta/immunology , Interleukin-1beta/metabolism , Intracellular Signaling Peptides and Proteins/immunology , Mice , Monocytes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Phosphate-Binding Proteins/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , THP-1 Cells
11.
Immunopharmacol Immunotoxicol ; 43(3): 247-258, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1238099

ABSTRACT

SARS-CoV-2 is a type of beta-CoV that develops acute pneumonia, which is an inflammatory condition. A cytokine storm has been recognized as one of the leading causes of death in patients with COVID-19. ALI and ARDS along with multiple organ failure have also been presented as the consequences of acute inflammation and cytokine storm. It has been previously confirmed that SARS-CoV, as another member of the beta-CoV family, activates NLRP3 inflammasome and consequently develops acute inflammation in a variety of ways through having complex interactions with the host immune system using structural and nonstructural proteins. Numerous studies conducted on Tranilast have further demonstrated that the given drug can act as an effective anti-chemotactic factor on controlling inflammation, and thus, it can possibly help the improvement of the acute form of COVID-19 by inhibiting some key inflammation-associated transcription factors such as NF-κB and impeding NLRP3 inflammasome. Several studies have comparably revealed the direct effect of this drug on the prevention of inappropriate tissue's remodeling; inhibition of neutrophils, IL-5, and eosinophils; repression of inflammatory cell infiltration into inflammation site; restriction of factors involved in acute airway inflammation like IL-33; and suppression of cytokine IL-13, which increase mucosal secretions. Therefore, Tranilast may be considered as a potential treatment for patients with the acute form of COVID-19 along with other drugs.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19/drug therapy , Inflammasomes/immunology , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , SARS-CoV-2/immunology , ortho-Aminobenzoates/therapeutic use , COVID-19/immunology , COVID-19/pathology , Humans
12.
Cells ; 10(4)2021 04 16.
Article in English | MEDLINE | ID: covidwho-1194613

ABSTRACT

Coronavirus disease 2019 (COVID-19) is the most devastating infectious disease in the 21st century with more than 2 million lives lost in less than a year. The activation of inflammasome in the host infected by SARS-CoV-2 is highly related to cytokine storm and hypercoagulopathy, which significantly contribute to the poor prognosis of COVID-19 patients. Even though many studies have shown the host defense mechanism induced by inflammasome against various viral infections, mechanistic interactions leading to downstream cellular responses and pathogenesis in COVID-19 remain unclear. The SARS-CoV-2 infection has been associated with numerous cardiovascular disorders including acute myocardial injury, myocarditis, arrhythmias, and venous thromboembolism. The inflammatory response triggered by the activation of NLRP3 inflammasome under certain cardiovascular conditions resulted in hyperinflammation or the modulation of angiotensin-converting enzyme 2 signaling pathways. Perturbations of several target cells and tissues have been described in inflammasome activation, including pneumocytes, macrophages, endothelial cells, and dendritic cells. The interplay between inflammasome activation and hypercoagulopathy in COVID-19 patients is an emerging area to be further addressed. Targeted therapeutics to suppress inflammasome activation may have a positive effect on the reduction of hyperinflammation-induced hypercoagulopathy and cardiovascular disorders occurring as COVID-19 complications.


Subject(s)
COVID-19/complications , Cardiovascular Diseases/etiology , Inflammasomes/immunology , Thrombophilia/etiology , Animals , COVID-19/immunology , COVID-19/pathology , Cardiovascular Diseases/immunology , Cardiovascular Diseases/pathology , Humans , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , SARS-CoV-2/immunology , Thrombophilia/immunology , Thrombophilia/pathology
13.
Blood Adv ; 5(5): 1523-1534, 2021 03 09.
Article in English | MEDLINE | ID: covidwho-1121096

ABSTRACT

Dysregulated immune response is the key factor leading to unfavorable coronavirus disease 2019 (COVID-19) outcome. Depending on the pathogen-associated molecular pattern, the NLRP3 inflammasome can play a crucial role during innate immunity activation. To date, studies describing the NLRP3 response during severe acute respiratory syndrome coronavirus 2 infection in patients are lacking. We prospectively monitored caspase-1 activation levels in peripheral myeloid cells from healthy donors and patients with mild to critical COVID-19. The caspase-1 activation potential in response to NLRP3 inflammasome stimulation was opposed between nonclassical monocytes and CD66b+CD16dim granulocytes in severe and critical COVID-19 patients. Unexpectedly, the CD66b+CD16dim granulocytes had decreased nigericin-triggered caspase-1 activation potential associated with an increased percentage of NLRP3 inflammasome impaired immature neutrophils and a loss of eosinophils in the blood. In patients who recovered from COVID-19, nigericin-triggered caspase-1 activation potential in CD66b+CD16dim cells was restored and the proportion of immature neutrophils was similar to control. Here, we reveal that NLRP3 inflammasome activation potential differs among myeloid cells and could be used as a biomarker of a COVID-19 patient's evolution. This assay could be a useful tool to predict patient outcome. This trial was registered at www.clinicaltrials.gov as #NCT04385017.


Subject(s)
COVID-19/blood , Inflammasomes/metabolism , Myeloid Cells/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , Biomarkers/blood , COVID-19/immunology , Case-Control Studies , Humans , Inflammasomes/blood , Middle Aged , Prospective Studies , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification
14.
Br J Pharmacol ; 177(21): 4921-4930, 2020 11.
Article in English | MEDLINE | ID: covidwho-991237

ABSTRACT

COVID-19, the illness caused by SARS-CoV-2, has a wide-ranging clinical spectrum that, in the worst-case scenario, involves a rapid progression to severe acute respiratory syndrome and death. Epidemiological data show that obesity and diabetes are among the main risk factors associated with high morbidity and mortality. The increased susceptibility to SARS-CoV-2 infection documented in obesity-related metabolic derangements argues for initial defects in defence mechanisms, most likely due to an elevated systemic metabolic inflammation ("metaflammation"). The NLRP3 inflammasome is a master regulator of metaflammation and has a pivotal role in the pathophysiology of either obesity or diabetes. Here, we discuss the most recent findings suggesting contribution of NLRP3 inflammasome to the increase in complications in COVID-19 patients with diabesity. We also review current pharmacological strategies for COVID-19, focusing on treatments whose efficacy could be due, at least in part, to interference with the activation of the NLRP3 inflammasome. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.


Subject(s)
Coronavirus Infections/drug therapy , Inflammasomes/immunology , Obesity/complications , Pneumonia, Viral/drug therapy , Betacoronavirus/isolation & purification , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/virology , Diabetes Mellitus/epidemiology , Disease Progression , Drug Repositioning , Humans , Inflammation/drug therapy , Inflammation/immunology , Inflammation/virology , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Risk Factors , SARS-CoV-2
15.
Front Immunol ; 11: 570251, 2020.
Article in English | MEDLINE | ID: covidwho-976246

ABSTRACT

Several countries around the world have faced an important obesity challenge for the past four decades as the result of an obesogenic environment. This disease has a multifactorial origin and it is associated with multiple comorbidities including type 2 diabetes, hypertension, osteoarthritis, metabolic syndrome, cancer, and dyslipidemia. With regard to dyslipidemia, hypertriglyceridemia is a well-known activator of the NLRP3 inflammasome, triggering adipokines and cytokines secretion which in addition induce a systemic inflammatory state that provides an adequate scenario for infections, particularly those mediated by viruses such as HIV, H1N1 influenza, and SARS-CoV-2. The SARS-CoV-2 infection causes the coronavirus disease 2019 (COVID-19) and it is responsible for the pandemic that we are currently living. COVID-19 causes an aggressive immune response known as cytokine release syndrome or cytokine storm that causes multiorgan failure and in most cases leads to death. In the present work, we aimed to review the molecular mechanisms by which obesity-associated systemic inflammation could cause a more severe clinical presentation of COVID-19. The SARS-CoV-2 infection could potentiate or accelerate the pre-existing systemic inflammatory state of individuals with obesity, via the NLRP3 inflammasome activation and the release of pro-inflammatory cytokines from cells trough Gasdermin-pores commonly found in cell death by pyroptosis.


Subject(s)
COVID-19/immunology , Cytokine Release Syndrome/immunology , Diabetes Mellitus, Type 2/immunology , Inflammasomes/immunology , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , SARS-CoV-2/physiology , Animals , COVID-19/genetics , COVID-19/virology , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/virology , Cytokines/genetics , Cytokines/immunology , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/virology , Humans , Inflammasomes/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , SARS-CoV-2/genetics
16.
Pathog Dis ; 79(1)2021 01 09.
Article in English | MEDLINE | ID: covidwho-963763

ABSTRACT

A vast proportion of coronavirus disease 2019 (COVID-19) individuals remain asymptomatic and can shed severe acute respiratory syndrome (SARS-CoV) type 2 virus to transmit the infection, which also explains the exponential increase in the number of COVID-19 cases globally. Furthermore, the rate of recovery from clinical COVID-19 in certain pockets of the globe is surprisingly high. Based on published reports and available literature, here, we speculated a few immunovirological mechanisms as to why a vast majority of individuals remain asymptomatic similar to exotic animal (bats and pangolins) reservoirs that remain refractile to disease development despite carrying a huge load of diverse insidious viral species, and whether such evolutionary advantage would unveil therapeutic strategies against COVID-19 infection in humans. Understanding the unique mechanisms that exotic animal species employ to achieve viral control, as well as inflammatory regulation, appears to hold key clues to the development of therapeutic versatility against COVID-19.


Subject(s)
COVID-19/immunology , Cytokine Release Syndrome/immunology , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , Receptors, KIR/immunology , Receptors, NK Cell Lectin-Like/immunology , Zoonoses/immunology , Animals , Animals, Exotic/virology , Asymptomatic Diseases , COVID-19/genetics , COVID-19/transmission , COVID-19/virology , Chiroptera/virology , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/prevention & control , Cytokine Release Syndrome/virology , Disease Reservoirs , Eutheria/virology , Gene Expression , Host Specificity , Humans , Immune Tolerance , Immunity, Innate , Interferon-beta/deficiency , Interferon-beta/genetics , Interferon-beta/immunology , Killer Cells, Natural/immunology , Killer Cells, Natural/virology , Monocytes/immunology , Monocytes/virology , NLR Family, Pyrin Domain-Containing 3 Protein/deficiency , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Receptors, KIR/deficiency , Receptors, KIR/genetics , Receptors, NK Cell Lectin-Like/deficiency , Receptors, NK Cell Lectin-Like/genetics , SARS-CoV-2/pathogenicity , Tumor Necrosis Factor-alpha/deficiency , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunology , Zoonoses/genetics , Zoonoses/transmission , Zoonoses/virology
17.
Basic Clin Pharmacol Toxicol ; 128(1): 37-45, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-889702

ABSTRACT

Curcumin is the effective ingredient of turmeric, sometimes used as a painkiller in traditional medicine. It has extensive biological properties such as anti-inflammatory and antioxidant activities. SARS-CoV-2 is a betacoronavirus developing severe pneumonitis. Inflammasome is one of the most important components of innate immunity, which exacerbates inflammation by increasing IL-1ß and IL-18 production. Studies on viral infections have shown overactivity of inflammasome and thus the occurrence of destructive and systemic inflammation in patients. NLRP3 inflammasome has been shown to play a key role in the pathogenesis of viral diseases. The proliferation of SARS-CoV-2 in a wide range of cells can be combined with numerous observations of direct and indirect activation of inflammasome by other coronaviruses. Activation of the inflammasome is likely to be involved in the formation of cytokine storm. Curcumin regulates several molecules in the intracellular signal transduction pathways involved in inflammation, including IBB, NF-kBERK1,2, AP-1, TGF-ß, TXNIP, STAT3, PPARγ, JAK2-STAT3, NLRP3, p38MAPK, Nrf2, Notch-1, AMPK, TLR-4 and MyD-88. Due to anti-inflammatory and anti-inflammasome properties without any special side effects, curcumin can potentially play a role in the treatment of COVID-19 infection along with other drug regimens.


Subject(s)
COVID-19 , Curcumin/pharmacology , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , SARS-CoV-2/drug effects , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , COVID-19/drug therapy , COVID-19/immunology , Humans , Inflammation/drug therapy , Inflammation/virology
19.
Life Sci ; 257: 118114, 2020 Sep 15.
Article in English | MEDLINE | ID: covidwho-651981

ABSTRACT

The world has witnessed a high morbidity and mortality caused by SARS-CoV-2, and global death toll is still rising. Exaggerated inflammatory responses are thought to be more responsible for infiltrated immune cells accumulation, organ damage especially lung, dyspnea, and respiratory failure rather than direct effect of viral replication. IL-6 and NLRP3 inflammasome are the major immune components in immune responses stimulation upon pathogen infection. It's noteworthy that the function and expression of these components are remarkably influenced by non-coding RNAs including long non-coding RNAs. Given the potential role of these components in organ damage and pathological manifestations of patients infected with COVID-19, their blockage might be a hopeful and promising treatment strategy. Notably, more study on long non-coding RNAs involved in inflammatory responses could elevate the efficacy of anti-inflammatory therapy. In this review we discuss the potential impact of IL-6 and NLRP3 inflammasome blocker drugs on inflammatory responses, viral clearance, and pathological and clinical manifestations. Collectively, anti-inflammatory strategy might pave the way to diminish clinical and pathological manifestations and thereby discharging patients infected with COVID-19 from hospital.


Subject(s)
Betacoronavirus/genetics , Coronavirus Infections/immunology , Interleukin-6/immunology , Pneumonia, Viral/immunology , RNA, Long Noncoding/physiology , Anti-Inflammatory Agents/pharmacology , Betacoronavirus/immunology , Betacoronavirus/metabolism , COVID-19 , Coronavirus Infections/metabolism , Cytokines/genetics , Cytokines/immunology , Humans , Inflammasomes/immunology , Inflammation/immunology , Interleukin-6/metabolism , Interleukin-6/pharmacology , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , Pandemics , Pneumonia, Viral/metabolism , RNA, Long Noncoding/genetics , SARS-CoV-2
20.
Front Immunol ; 11: 1580, 2020.
Article in English | MEDLINE | ID: covidwho-647056

ABSTRACT

SARS-CoV-2 might directly activate NLRP3 inflammasome resulting in an endogenous adjuvant activity necessary to mount a proper adaptive immune response against the virus. Heterogeneous response of COVID-19 patients could be attributed to differences in not being able to properly downregulate NLRP3 inflammasome activation. This relates to the fitness of the immune system of the individual challenged by the virus. Patients with a reduced immune fitness can demonstrate a dysregulated NLRP3 inflammasome activity resulting in severe COVID-19 with tissue damage and a cytokine storm. We sketch the outlines of five possible scenarios for COVID-19 in medical practice and provide potential treatment options targeting dysregulated endogenous adjuvant activity in severe COVID-19 patients.


Subject(s)
Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , HMGB1 Protein/metabolism , Inflammasomes/immunology , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Betacoronavirus/immunology , COVID-19 , Coronavirus Infections/pathology , Cytokines/metabolism , Humans , Macrophage Activation/immunology , Macrophages/immunology , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors , Neutrophil Infiltration/immunology , Neutrophils/immunology , Pandemics , Pneumonia, Viral/pathology , SARS-CoV-2
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