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1.
J Trop Pediatr ; 68(2)2022 02 03.
Article in English | MEDLINE | ID: covidwho-1702787

ABSTRACT

Predictors of early diagnosis and severe infection in children with coronavirus disease 2019 (COVID-19), which has killed more than 4 million people worldwide, have not been identified. However, some biomarkers, including cytokines and chemokines, are associated with the diagnosis, pathogenesis and severity of COVID-19 in adults. We examined whether such biomarkers can be used to predict the diagnosis and prognosis of COVID-19 in pediatric patients. Eighty-nine children were included in the study, comprising three patient groups of 69 patients (6 severe, 36 moderate and 27 mild) diagnosed with COVID-19 by real-time polymerase chain reaction observed for 2-216 months and clinical findings and 20 healthy children in the same age group. Hemogram, coagulation, inflammatory parameters and serum levels of 16 cytokines and chemokines were measured in blood samples and were analyzed and compared with clinical data. Interleukin 1-beta (IL-1ß), interleukin-12 (IL-12) and interferon gamma-induced protein 10 (IP-10) levels were significantly higher in the COVID-19 patients (p = 0.035, p = 0.006 and p < 0.001). Additionally, D-dimer and IP-10 levels were higher in the severe group (p = 0.043 for D-dimer, area under the curve = 0.743, p = 0.027 for IP-10). Lymphocytes, C-reactive protein and procalcitonin levels were not diagnostic or prognostic factors in pediatric patients (p = 0.304, p = 0.144 and p = 0.67). Increased IL-1ß, IL-12 and IP-10 levels in children with COVID-19 are indicators for early diagnosis, and D-dimer and IP-10 levels are predictive of disease severity. In children with COVID-19, these biomarkers can provide information on prognosis and enable early treatment.


Subject(s)
Biomarkers , COVID-19 , Cytokines/blood , Biomarkers/blood , COVID-19/diagnosis , Chemokine CXCL10 , Chemokines/blood , Child , Fibrin Fibrinogen Degradation Products , Humans , Interleukin-12 , Interleukin-1beta , Prognosis , SARS-CoV-2 , Severity of Illness Index
2.
Stem Cell Reports ; 17(3): 538-555, 2022 03 08.
Article in English | MEDLINE | ID: covidwho-1692861

ABSTRACT

To date, the direct causative mechanism of SARS-CoV-2-induced endotheliitis remains unclear. Here, we report that human ECs barely express surface ACE2, and ECs express less intracellular ACE2 than non-ECs of the lungs. We ectopically expressed ACE2 in hESC-ECs to model SARS-CoV-2 infection. ACE2-deficient ECs are resistant to the infection but are more activated than ACE2-expressing ones. The virus directly induces endothelial activation by increasing monocyte adhesion, NO production, and enhanced phosphorylation of p38 mitogen-associated protein kinase (MAPK), NF-κB, and eNOS in ACE2-expressing and -deficient ECs. ACE2-deficient ECs respond to SARS-CoV-2 through TLR4 as treatment with its antagonist inhibits p38 MAPK/NF-κB/ interleukin-1ß (IL-1ß) activation after viral exposure. Genome-wide, single-cell RNA-seq analyses further confirm activation of the TLR4/MAPK14/RELA/IL-1ß axis in circulating ECs of mild and severe COVID-19 patients. Circulating ECs could serve as biomarkers for indicating patients with endotheliitis. Together, our findings support a direct role for SARS-CoV-2 in mediating endothelial inflammation in an ACE2-dependent or -independent manner.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Models, Biological , SARS-CoV-2/physiology , Toll-Like Receptor 4/metabolism , Angiotensin-Converting Enzyme 2/genetics , COVID-19/pathology , COVID-19/virology , Endothelial Cells/cytology , Endothelial Cells/metabolism , Gene Expression Profiling , Human Umbilical Vein Endothelial Cells , Humans , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , NF-kappa B/antagonists & inhibitors , NF-kappa B/genetics , NF-kappa B/metabolism , Pluripotent Stem Cells/cytology , Pluripotent Stem Cells/metabolism , SARS-CoV-2/isolation & purification , Severity of Illness Index , Single-Cell Analysis , Toll-Like Receptor 4/antagonists & inhibitors , Toll-Like Receptor 4/genetics , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , p38 Mitogen-Activated Protein Kinases/genetics , p38 Mitogen-Activated Protein Kinases/metabolism
3.
Front Immunol ; 12: 734279, 2021.
Article in English | MEDLINE | ID: covidwho-1686469

ABSTRACT

Newly emerging variants of coronavirus 2 (SARS-CoV-2) raise concerns about the spread of the disease, and with the rising case numbers, the Coronavirus disease 2019 (COVID-19) remains a challenging medical emergency towards the end of the year 2021. Swiftly developed novel vaccines aid in the prevention of the spread, and it seems that a specific cure will not be at hand soon. The prognosis of COVID-19 in patients with autoimmune/autoinflammatory rheumatic diseases (AIIRD) is more severe when compared to the otherwise healthy population, and vaccination is essential. Evidence for both the efficacy and safety of COVID-19 vaccination in AIIRD under immunosuppression is accumulating, but the effect of Interleukin-1 on vaccination in general and in AIIRD patients is rarely addressed in the current literature. In light of the current literature, it seems that the level of agreement on the timing of COVID-19 vaccination is moderate in patients using IL-1 blockers, and expert opinions may vary. Generally, it may be recommended that patients under IL-1 blockade can be vaccinated without interrupting the anti-cytokine therapy, especially in patients with ongoing high disease activity to avoid disease relapses. However, in selected cases, after balancing for disease activity and risk of relapses, vaccination may be given seven days after the drug levels have returned to baseline, especially for IL-1 blocking agents with long half-lives such as canakinumab and rilonacept. This may help to ensure an ideal vaccine response in the face of the possibility that AIIRD patients may develop a more pronounced and severe COVID-19 disease course.


Subject(s)
Antirheumatic Agents/adverse effects , COVID-19 Vaccines/immunology , COVID-19/prevention & control , Interleukin-1beta/antagonists & inhibitors , Rheumatic Diseases/drug therapy , SARS-CoV-2/immunology , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , Antirheumatic Agents/therapeutic use , Autoimmune Diseases/drug therapy , Autoimmune Diseases/immunology , Humans , Immunosuppressive Agents/adverse effects , Immunosuppressive Agents/therapeutic use , Recombinant Fusion Proteins/adverse effects , Recombinant Fusion Proteins/therapeutic use , Rheumatic Diseases/immunology , Vaccination
4.
Front Immunol ; 12: 799558, 2021.
Article in English | MEDLINE | ID: covidwho-1662582

ABSTRACT

The poor outcome of the coronavirus disease-2019 (COVID-19), caused by SARS-CoV-2, is associated with systemic hyperinflammatory response and immunopathology. Although inflammasome and oxidative stress have independently been implicated in COVID-19, it is poorly understood whether these two pathways cooperatively contribute to disease severity. Herein, we found an enrichment of CD14highCD16- monocytes displaying inflammasome activation evidenced by caspase-1/ASC-speck formation in severe COVID-19 patients when compared to mild ones and healthy controls, respectively. Those cells also showed aberrant levels of mitochondrial superoxide and lipid peroxidation, both hallmarks of the oxidative stress response, which strongly correlated with caspase-1 activity. In addition, we found that NLRP3 inflammasome-derived IL-1ß secretion by SARS-CoV-2-exposed monocytes in vitro was partially dependent on lipid peroxidation. Importantly, altered inflammasome and stress responses persisted after short-term patient recovery. Collectively, our findings suggest oxidative stress/NLRP3 signaling pathway as a potential target for host-directed therapy to mitigate early COVID-19 hyperinflammation and also its long-term outcomes.


Subject(s)
COVID-19/metabolism , Inflammasomes/metabolism , Lipopolysaccharide Receptors/metabolism , Monocytes/metabolism , Oxidative Stress/physiology , Receptors, IgG/metabolism , Aged , COVID-19/pathology , Caspase 1/metabolism , Female , GPI-Linked Proteins/metabolism , Humans , Interleukin-1beta/metabolism , Male , Middle Aged , Mitochondria/metabolism , Mitochondria/pathology , Monocytes/pathology , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , SARS-CoV-2/metabolism , Signal Transduction/physiology
5.
Nutrients ; 14(2)2022 Jan 07.
Article in English | MEDLINE | ID: covidwho-1613925

ABSTRACT

Despite the ongoing vaccination efforts, there is still an urgent need for safe and effective treatments to help curb the debilitating effects of COVID-19 disease. This systematic review aimed to investigate the efficacy of supplemental curcumin treatment on clinical outcomes and inflammation-related biomarker profiles in COVID-19 patients. We searched PubMed, Scopus, Web of Science, EMBASE, ProQuest, and Ovid databases up to 30 June 2021 to find studies that assessed the effects of curcumin-related compounds in mild to severe COVID-19 patients. Six studies were identified which showed that curcumin supplementation led to a significant decrease in common symptoms, duration of hospitalization and deaths. In addition, all of these studies showed that the intervention led to amelioration of cytokine storm effects thought to be a driving force in severe COVID-19 cases. This was seen as a significant (p < 0.05) decrease in proinflammatory cytokines such as IL1ß and IL6, with a concomitant significant (p < 0.05) increase in anti-inflammatory cytokines, including IL-10, IL-35 and TGF-α. Taken together, these findings suggested that curcumin exerts its beneficial effects through at least partial restoration of pro-inflammatory/anti-inflammatory balance. In conclusion, curcumin supplementation may offer an efficacious and safe option for improving COVID-19 disease outcomes. We highlight the point that future clinical studies of COVID-19 disease should employ larger cohorts of patients in different clinical settings with standardized preparations of curcumin-related compounds.


Subject(s)
COVID-19/drug therapy , Curcumin/administration & dosage , Dietary Supplements , Hospitalization , Phytotherapy/methods , Curcumin/pharmacology , Cytokines/metabolism , Female , Humans , Inflammation Mediators/metabolism , Interleukin-10/metabolism , Interleukin-1beta/metabolism , Interleukin-6/metabolism , Interleukins/metabolism , Male , Patient Acuity , Transforming Growth Factor alpha/metabolism , Treatment Outcome
6.
Front Immunol ; 12: 781352, 2021.
Article in English | MEDLINE | ID: covidwho-1613552

ABSTRACT

After the outburst of the SARS-CoV-2 pandemic, a worldwide research effort has led to the uncovering of many aspects of the COVID-19, among which we can count the outstanding role played by inflammatory cytokine milieu in the disease progression. Despite that, molecular mechanisms that regulate SARS-CoV-2 pathogenesis are still almost unidentified. In this study, we investigated whether the pro-inflammatory milieu of the host affects the susceptibility of SARS-CoV-2 infection by modulating ACE2 and TMPRSS2 expression. Our results indicated that the host inflammatory milieu favors SARS-CoV-2 infection by directly increasing TMPRSS2 expression. We unveiled the molecular mechanism that regulates this process and that can be therapeutically advantageously targeted.


Subject(s)
GATA2 Transcription Factor/metabolism , Interleukin-1beta/metabolism , SARS-CoV-2/pathogenicity , Serine Endopeptidases/metabolism , Virus Internalization , A549 Cells , COVID-19 , Humans , p38 Mitogen-Activated Protein Kinases/metabolism
7.
Sci Rep ; 11(1): 24432, 2021 12 24.
Article in English | MEDLINE | ID: covidwho-1585772

ABSTRACT

Despite the initial success of some drugs and vaccines targeting COVID-19, understanding the mechanism underlying SARS-CoV-2 disease pathogenesis remains crucial for the development of further approaches to treatment. Some patients with severe Covid-19 experience a cytokine storm and display evidence of inflammasome activation leading to increased levels of IL-1ß and IL-18; however, other reports have suggested reduced inflammatory responses to Sars-Cov-2. In this study we have examined the effects of the Sars-Cov-2 envelope (E) protein, a virulence factor in coronaviruses, on inflammasome activation and pulmonary inflammation. In cultured macrophages the E protein suppressed inflammasome priming and NLRP3 inflammasome activation. Similarly, in mice transfected with E protein and treated with poly(I:C) to simulate the effects of viral RNA, the E protein, in an NLRP3-dependent fashion, reduced expression of pro-IL-1ß, levels of IL-1ß and IL-18 in broncho-alveolar lavage fluid, and macrophage infiltration in the lung. To simulate the effects of more advanced infection, macrophages were treated with both LPS and poly(I:C). In this setting the E protein increased NLRP3 inflammasome activation in both murine and human macrophages. Thus, the Sars-Cov-2 E protein may initially suppress the host NLRP3 inflammasome response to viral RNA while potentially increasing NLRP3 inflammasome responses in the later stages of infection. Targeting the Sars-Cov-2 E protein especially in the early stages of infection may represent a novel approach to Covid-19 therapy.


Subject(s)
Coronavirus Envelope Proteins/metabolism , Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , SARS-CoV-2/metabolism , Animals , Bronchoalveolar Lavage Fluid/chemistry , COVID-19/pathology , COVID-19/virology , Coronavirus Envelope Proteins/genetics , Down-Regulation/drug effects , Endoplasmic Reticulum Stress , Humans , Inflammasomes/drug effects , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Janus Kinases/genetics , Janus Kinases/metabolism , Lipopolysaccharides/pharmacology , Macrophages/cytology , Macrophages/drug effects , Macrophages/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , NLR Family, Pyrin Domain-Containing 3 Protein/deficiency , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Poly I-C/pharmacology , RNA, Viral/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/isolation & purification
9.
Int J Immunopathol Pharmacol ; 35: 20587384211059675, 2021.
Article in English | MEDLINE | ID: covidwho-1582485

ABSTRACT

INTRODUCTION: The fully-human monoclonal anti-interleukin (IL)-1ß antibody canakinumab may inhibit the production of inflammatory mediators in patients with coronavirus disease 2019 (COVID-19) and the hyperinflammatory response potentially leading to acute respiratory distress syndrome. OBJECTIVES: The goal of our retrospective, observational analysis was to evaluate the safety and efficacy of subcutaneous (s.c.) canakinumab in combination with our standard of care (SOC) treatment of selected patients with COVID-19 with respiratory failure and elevated reactive pro-inflammatory markers. METHODS: Eight participants received two doses of s.c. canakinumab 150 mg (or 2 mg/kg for participants weighing ≤40 kg) in addition to SOC. 12 patients received only SOC treatment. RESULTS: Canakinumab treatment reduced the need for mechanical ventilation and reduced proinflammatory markers, resulting in an amelioration of the final outcome, with respect to the control group who received SOC alone. The treatment was safe and well tolerated; no adverse events were reported. CONCLUSION: The use of canakinumab (300 mg, s.c.) in the early stage of COVID-19 with mild-to-moderate respiratory failure was superior to SOC at preventing clinical deterioration and may warrant further investigation as a treatment option for patients with COVID-19 who experience a hyperinflammatory response in the early stage of the disease.


Subject(s)
Antibodies, Monoclonal, Humanized , COVID-19 , Interleukin-1beta , Respiration, Artificial , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/immunology , Biomarkers/blood , COVID-19/complications , COVID-19/epidemiology , COVID-19/immunology , COVID-19/therapy , Dose-Response Relationship, Drug , Female , Humans , Inflammation Mediators/blood , Interleukin-1beta/antagonists & inhibitors , Interleukin-1beta/immunology , Italy/epidemiology , Male , Middle Aged , Monitoring, Immunologic/methods , Outcome and Process Assessment, Health Care , Patient Selection , Respiration, Artificial/methods , Respiration, Artificial/statistics & numerical data , Retrospective Studies , SARS-CoV-2 , Time-to-Treatment
10.
Arch Virol ; 166(12): 3301-3310, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1575784

ABSTRACT

Currently, the world is witnessing the pandemic of COVID-19, a disease caused by the novel coronavirus SARS-CoV-2. Reported differences in clinical manifestations and outcomes in SARS-CoV-2 infection could be attributed to factors such as virus replication, infiltration of inflammatory cells, and altered cytokine production. Virus-induced aberrant and excessive cytokine production has been linked to the morbidity and mortality of several viral infections. Using a Luminex platform, we investigated plasma cytokine and chemokine levels of 27 analytes from hospitalized asymptomatic (n = 39) and mildly symptomatic (n = 35) SARS-CoV-2-infected patients (in the early phase of infection), recovered individuals (45-60 days postinfection) (n = 40), and uninfected controls (n = 36) from the city of Pune located in the state of Maharashtra in India. Levels of the pro-inflammatory cytokines IL-1ß, IL-6, and TNF-α and the chemokine CXCL-10 were significantly higher, while those of the antiviral cytokines IFN-γ and IL-12 p70 were significantly lower in both asymptomatic and mildly symptomatic patients than in controls. Comparison among the patient categories revealed no difference in the levels of the cytokines/chemokines except for CXCL-10 being significantly higher and IL-17, IL-4, and VEGF being significantly lower in the mildly symptomatic patients. Interestingly, levels of all key analytes were significantly lower in recovered individuals than in those in both patient categories. Nevertheless, the level of CXCL10 was significantly higher in the recovered patients than in the controls, indicating that the immune system of SARS-CoV-2 patients may take a longer time to normalize. Our data suggest that IL-6, IL-1ß, TNF-α, CXCL-10, and reduced antiviral cytokines could be used as biomarkers of SARS-CoV-2 infection.


Subject(s)
COVID-19 , Chemokines/immunology , Cytokines/immunology , Biomarkers/blood , COVID-19/diagnosis , COVID-19/immunology , Chemokine CXCL10 , Humans , India/epidemiology , Interleukin-1beta , Interleukin-6 , Tumor Necrosis Factor-alpha
11.
Viruses ; 13(12)2021 12 14.
Article in English | MEDLINE | ID: covidwho-1572670

ABSTRACT

SARS-CoV-2 is a new type of coronavirus that has caused worldwide pandemic. The disease induced by SARS-CoV-2 is called COVID-19. A majority of people with COVID-19 have relatively mild respiratory symptoms. However, a small percentage of COVID-19 patients develop a severe disease where multiple organs are affected. These severe forms of SARS-CoV-2 infections are associated with excessive production of pro-inflammatory cytokines, so called "cytokine storm". Inflammasomes, which are protein complexes of the innate immune system orchestrate development of local and systemic inflammation during virus infection. Recent data suggest involvement of inflammasomes in severe COVID-19. Activation of inflammasome exerts two major effects: it activates caspase-1-mediated processing and secretion of pro-inflammatory cytokines IL-1ß and IL-18, and induces inflammatory cell death, pyroptosis, via protein called gasdermin D. Here, we provide comprehensive review of current understanding of the activation and possible functions of different inflammasome structures during SARS-CoV-2 infection and compare that to response caused by influenza A virus. We also discuss how novel SARS-CoV-2 mRNA vaccines activate innate immune response, which is a prerequisite for the activation of protective adaptive immune response.


Subject(s)
COVID-19/immunology , Inflammasomes/immunology , Adaptive Immunity , COVID-19 Vaccines , Cell Death , Cytokine Release Syndrome , Cytokines/immunology , Humans , Immunity, Innate , Inflammation , Interleukin-18 , Interleukin-1beta , Neoplasm Proteins , Pyroptosis , SARS-CoV-2/immunology
12.
Sci Rep ; 11(1): 23695, 2021 12 08.
Article in English | MEDLINE | ID: covidwho-1561520

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread across the world. Inactivating the virus in saliva and the oral cavity represents a reasonable approach to prevent human-to-human transmission because the virus is easily transmitted through oral routes by dispersed saliva. Persimmon-derived tannin is a condensed type of tannin that has strong antioxidant and antimicrobial activity. In this study, we investigated the antiviral effects of persimmon-derived tannin against SARS-CoV-2 in both in vitro and in vivo models. We found that persimmon-derived tannin suppressed SARS-CoV-2 titers measured by plaque assay in vitro in a dose- and time-dependent manner. We then created a Syrian hamster model by inoculating SARS-CoV-2 into hamsters' mouths. Oral administration of persimmon-derived tannin dissolved in carboxymethyl cellulose before virus inoculation dramatically reduced the severity of pneumonia with lower virus titers compared with a control group inoculated with carboxymethyl cellulose alone. In addition, pre-administration of tannin to uninfected hamsters reduced hamster-to-hamster transmission of SARS-CoV-2 from a cohoused, infected donor cage mate. These data suggest that oral administration of persimmon-derived tannin may help reduce the severity of SARS-CoV-2 infection and transmission of the virus.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Diospyros/chemistry , Tannins/therapeutic use , Administration, Oral , Animals , Antiviral Agents/chemistry , Antiviral Agents/isolation & purification , Antiviral Agents/pharmacology , COVID-19/pathology , COVID-19/transmission , COVID-19/virology , Cricetinae , Diospyros/metabolism , Disease Models, Animal , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Interleukin-6/genetics , Interleukin-6/metabolism , Lung/pathology , Lung/virology , Male , Mesocricetus , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Severity of Illness Index , Tannins/chemistry , Tannins/isolation & purification , Tannins/pharmacology , Viral Load/drug effects
13.
Front Immunol ; 12: 750969, 2021.
Article in English | MEDLINE | ID: covidwho-1551506

ABSTRACT

The COVID-19 is an infectious disease caused by SARS-CoV-2 infection. A large number of clinical studies found high-level expression of pro-inflammatory cytokines in patients infected with SARS-CoV-2, which fuels the rapid development of the disease. However, the specific molecular mechanism is still unclear. In this study, we found that SARS-CoV-2 Nsp5 can induce the expression of cytokines IL-1ß, IL-6, TNF-α, and IL-2 in Calu-3 and THP1 cells. Further research found that Nsp5 enhances cytokine expression through activating the NF-κB signaling pathway. Subsequently, we investigated the upstream effectors of the NF-κB signal pathway on Nsp5 overexpression and discovered that Nsp5 increases the protein level of MAVS. Moreover, Nsp5 can promote the SUMOylation of MAVS to increase its stability and lead to increasing levels of MAVS protein, finally triggering activation of NF-κB signaling. The knockdown of MAVS and the inhibitor of SUMOylation treatment can attenuate Nsp5-mediated NF-κB activation and cytokine induction. We identified a novel role of SARS-CoV-2 Nsp5 to enhance cytokine production by activating the NF-κB signaling pathway.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Coronavirus 3C Proteases/immunology , Cytokines/biosynthesis , NF-kappa B/metabolism , SARS-CoV-2/immunology , Sumoylation/physiology , Adaptor Proteins, Signal Transducing/genetics , Animals , COVID-19/immunology , Cell Line , Chlorocebus aethiops , Enzyme Activation/drug effects , HEK293 Cells , Humans , Immunity, Innate/immunology , Interleukin-1beta/biosynthesis , Interleukin-2/biosynthesis , Interleukin-6/biosynthesis , Signal Transduction/physiology , Sumoylation/drug effects , THP-1 Cells , Tumor Necrosis Factor-alpha/biosynthesis , Vero Cells
14.
J Immunol Res ; 2021: 8214656, 2021.
Article in English | MEDLINE | ID: covidwho-1546598

ABSTRACT

Dengue fever is an infection by the dengue virus (DENV) transmitted by vector mosquitoes. It causes many infections in tropical and subtropical countries every year, thus posing a severe disease threat. Cytokine storms, one condition where many proinflammatory cytokines are mass-produced, might lead to cellular dysfunction in tissue/organ failures and often facilitate severe dengue disease in patients. Interleukin- (IL-) 18, similar to IL-1ß, is a proinflammatory cytokine produced during inflammation following inflammasome activation. Inflammatory stimuli, including microbial infections, damage signals, and cytokines, all induce the production of IL-18. High serum IL-18 is remarkably correlated with severely ill dengue patients; however, its possible roles have been less explored. Based on the clinical and basic findings, this review discusses the potential immunopathogenic role of IL-18 when it participates in DENV infection and dengue disease progression based on existing findings and related past studies.


Subject(s)
Dengue Virus/physiology , Dengue/immunology , Inflammasomes/metabolism , Inflammation/immunology , Interleukin-18/immunology , Aedes , Animals , Disease Vectors , Humans , Interleukin-1beta/immunology
15.
Biomedica ; 41(Sp. 2): 86-102, 2021 10 15.
Article in English, Spanish | MEDLINE | ID: covidwho-1529016

ABSTRACT

INTRODUCTION: Immunological markers have been described during COVID-19 and persist after recovery. These immune markers are associated with clinical features among SARSCoV-2 infected individuals. Nevertheless, studies reporting a comprehensive analysis of the immune changes occurring during SARS-CoV-2 infection are still limited. OBJECTIVE: To evaluate the production of proinflammatory cytokines, the antibody response, and the phenotype and function of NK cells and T cells in a Colombian family cluster with SARS-CoV-2 infection. MATERIALS AND METHODS: Proinflammatory cytokines were evaluated by RT-PCR and ELISA. The frequency, phenotype, and function of NK cells (cocultures with K562 cells) and T-cells (stimulated with spike/RdRp peptides) were assessed by flow cytometry. Anti-SARS-CoV-2 antibodies were determined using indirect immunofluorescence and plaque reduction neutralization assay. RESULTS: During COVID-19, we observed a high proinflammatory-cytokine production and a reduced CD56bright-NK cell and cytotoxic response. Compared with healthy controls, infected individuals had a higher frequency of dysfunctional CD8+ T cells CD38+HLA-DR-. During the acute phase, CD8+ T cells stimulated with viral peptides exhibited a monofunctional response characterized by high IL-10 production. However, during recovery, we observed a bifunctional response characterized by the co-expression of CD107a and granzyme B or perforin. CONCLUSION: Although the proinflammatory response is a hallmark of SARS-CoV-2 infection, other phenotypic and functional alterations in NK cells and CD8+ T cells could be associated with the outcome of COVID-19. However, additional studies are required to understand these alterations and to guide future immunotherapy strategies.


Introducción. Se han descrito diferentes marcadores inmunológicos durante la COVID-19, los cuales persisten incluso después de la convalecencia y se asocian con los estadios clínicos de la infección. Sin embargo, aún son pocos los estudios orientados al análisis exhaustivo de las alteraciones del sistema inmunológico en el curso de la infección. Objetivo. Evaluar la producción de citocinas proinflamatorias, la reacción de anticuerpos, y el fenotipo y la función de las células NK y los linfocitos T en una familia colombiana con infección por SARS-CoV-2. Materiales y métodos. Se evaluaron las citocinas proinflamatorias mediante RT-PCR y ELISA; la frecuencia, el fenotipo y la función de las células NK (en cocultivos con células K562) y linfocitos T CD8+ (estimulados con péptidos spike/RdRp) mediante citometría de flujo, y los anticuerpos anti-SARS-CoV-2, mediante inmunofluorescencia indirecta y prueba de neutralización por reducción de placa. Resultados. Durante la COVID-19 hubo una producción elevada de citocinas proinflamatorias, con disminución de las células NK CD56bright y reacción citotóxica. Comparados con los controles sanos, los individuos infectados presentaron con gran frecuencia linfocitos T CD8+ disfuncionales CD38+HLA-DR-. Además, en los linfocitos T CD8+ estimulados con péptidos virales, predominó una reacción monofuncional con gran producción de IL-10 durante la fase aguda y una reacción bifuncional caracterizada por la coexpresión de CD107a y granzima B o perforina durante la convalecencia. Conclusión. Aunque la reacción inflamatoria caracteriza la infección por SARS-CoV-2, hay otras alteraciones fenotípicas y funcionales en células NK y linfocitos T CD8+ que podrían asociarse con la progresión de la infección. Se requieren estudios adicionales para entender estas alteraciones y guiar futuras estrategias de inmunoterapia.


Subject(s)
COVID-19/immunology , Killer Cells, Natural , SARS-CoV-2/immunology , T-Lymphocytes , Adult , Antibodies, Viral/analysis , CD56 Antigen/immunology , Case-Control Studies , Colombia , Family Health , Granzymes/metabolism , Humans , Interleukin-10/metabolism , Interleukin-1beta/blood , Interleukin-6/blood , Interleukin-8/blood , K562 Cells , Killer Cells, Natural/cytology , Killer Cells, Natural/immunology , Lymphocyte Activation , Male , Middle Aged , Perforin/metabolism , Phenotype , Receptors, CCR7/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/immunology , Tumor Necrosis Factor-alpha/blood , Young Adult
16.
Med Sci Monit ; 27: e934365, 2021 Nov 19.
Article in English | MEDLINE | ID: covidwho-1527017

ABSTRACT

BACKGROUND Autologous blood-derived products can target specific inflammatory molecular pathways and have potentially beneficial therapeutic effects on inflammatory pathologies. The purpose of this study was to assess in vitro the anti-inflammatory and anti-catabolic potential of an autologous blood product as a possible treatment for COVID-19-induced cytokine storm. MATERIAL AND METHODS Blood samples from healthy donors and donors who had recovered from COVID-19 were incubated using different techniques and analyzed for the presence of anti-inflammatory, anti-catabolic, regenerative, pro-inflammatory, and procatabolic molecules. RESULTS The highest concentrations of therapeutic molecules for targeting inflammatory pathways were found in the blood that had been incubated for 24 h at 37°C, whereas a significant increase was observed after 6 h of incubation in blood from COVID-19-recovered donors. Beneficially, the 6-h incubation process did not downregulate anti-COVID-19 immunoglobulin G concentrations. Unfortunately, increases in matrix metalloproteinase 9, tumor necrosis factor alpha, and interleukin-1 were detected in the product after incubation; however, these increases could be blocked by adding citric acid, with no effect on the concentration of the target therapeutic molecules. Our data allow for safer and more effective future treatments. CONCLUSIONS An autologous blood-derived product containing anti-inflammatory and anti-catabolic molecules, which we term Cytorich, has a promising therapeutic role in the treatment of a virus-induced cytokine storm, including that associated with COVID-19.


Subject(s)
Anabolic Agents/blood , Anti-Inflammatory Agents/blood , COVID-19/complications , Cytokine Release Syndrome/drug therapy , Adult , Anabolic Agents/isolation & purification , Anabolic Agents/therapeutic use , Anti-Inflammatory Agents/isolation & purification , Anti-Inflammatory Agents/therapeutic use , COVID-19/blood , COVID-19/drug therapy , Cytokine Release Syndrome/etiology , Female , Humans , Interleukin-1beta/antagonists & inhibitors , Male , Matrix Metalloproteinase 9/metabolism , Metabolism/drug effects , Middle Aged , Young Adult
17.
Eur Rev Med Pharmacol Sci ; 25(21): 6797-6812, 2021 11.
Article in English | MEDLINE | ID: covidwho-1524867

ABSTRACT

Cytokines in cardiac tissue plays a key role in progression of cardiometabolic diseases and cardiotoxicity induced by several anticancer drugs. Interleukin-1ß is one on the most studied regulator of cancer progression, survival and resistance to anticancer treatments. Recent findings indicate that interleukin1-ß exacerbates myocardial damages in cancer patients treated with chemotherapies and immune check-point inhibitors. Interleukin1-ß blocking agent canakinumab reduces major adverse cardiovascular events and cardiovascular death in recent cardiovascular trials. We focalized on the main biological functions of interleukin1-ß in cancer and cardiovascular diseases, summarizing the main clinical evidence available to date in literature. Especially in the era of SARS-CoV-2 infection, associated to coagulopathies, myocarditis and heart failure, cancer patients have an increased risk of cardiovascular complications compared to general population, therefore, the pharmacological inhibition of interleukin1-ß should be discussed and considered.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents/adverse effects , COVID-19/complications , Cardiotoxicity/prevention & control , Interleukin-1beta/metabolism , Neoplasms/drug therapy , Anthracyclines/adverse effects , Anthracyclines/therapeutic use , Antibodies, Monoclonal, Humanized/immunology , Antineoplastic Agents/therapeutic use , COVID-19/virology , Cardiotoxicity/etiology , Cardiovascular Diseases/prevention & control , Humans , Interleukin-1beta/immunology , Neoplasms/complications , SARS-CoV-2/isolation & purification
18.
JCI Insight ; 6(24)2021 12 22.
Article in English | MEDLINE | ID: covidwho-1518198

ABSTRACT

A substantial proportion of patients who have recovered from coronavirus disease-2019 (COVID-19) experience COVID-19-related symptoms even months after hospital discharge. We extensively immunologically characterized patients who recovered from COVID-19. In these patients, T cells were exhausted, with increased PD-1+ T cells, as compared with healthy controls. Plasma levels of IL-1ß, IL-1RA, and IL-8, among others, were also increased in patients who recovered from COVID-19. This altered immunophenotype was mirrored by a reduced ex vivo T cell response to both nonspecific and specific stimulation, revealing a dysfunctional status of T cells, including a poor response to SARS-CoV-2 antigens. Altered levels of plasma soluble PD-L1, as well as of PD1 promoter methylation and PD1-targeting miR-15-5p, in CD8+ T cells were also observed, suggesting abnormal function of the PD-1/PD-L1 immune checkpoint axis. Notably, ex vivo blockade of PD-1 nearly normalized the aforementioned immunophenotype and restored T cell function, reverting the observed post-COVID-19 immune abnormalities; indeed, we also noted an increased T cell-mediated response to SARS-CoV-2 peptides. Finally, in a neutralization assay, PD-1 blockade did not alter the ability of T cells to neutralize SARS-CoV-2 spike pseudotyped lentivirus infection. Immune checkpoint blockade ameliorates post-COVID-19 immune abnormalities and stimulates an anti-SARS-CoV-2 immune response.


Subject(s)
COVID-19/complications , Cytokines/immunology , Immune Checkpoint Inhibitors/pharmacology , Programmed Cell Death 1 Receptor/immunology , SARS-CoV-2/immunology , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , B7-H1 Antigen/immunology , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Case-Control Studies , Cytokines/drug effects , DNA Methylation , Female , Humans , Immunophenotyping , In Vitro Techniques , Interleukin 1 Receptor Antagonist Protein/drug effects , Interleukin 1 Receptor Antagonist Protein/immunology , Interleukin-1beta/drug effects , Interleukin-1beta/immunology , Interleukin-8/drug effects , Interleukin-8/immunology , Male , MicroRNAs/metabolism , Middle Aged , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Promoter Regions, Genetic
19.
Eur J Med Chem ; 229: 114002, 2022 Feb 05.
Article in English | MEDLINE | ID: covidwho-1517139

ABSTRACT

Compounds targeting the inflammasome-caspase-1 pathway could be of use for the treatment of inflammation and inflammatory diseases. Previous caspase-1 inhibitors were in great majority covalent inhibitors and failed in clinical trials. Using a mixed modelling, computational screening, synthesis and in vitro testing approach, we identified a novel class of non-covalent caspase-1 non cytotoxic inhibitors which are able to inhibit IL-1ß release in activated macrophages in the low µM range, in line with the best activities observed for the known covalent inhibitors. Our compounds could form the basis of further optimization towards potent drugs for the treatment of inflammation and inflammatory disorders including also dysregulated inflammation in Covid 19.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Autoimmune Diseases/drug therapy , Caspase 1/drug effects , Inflammasomes/drug effects , Inflammation/drug therapy , Serpins/chemical synthesis , Serpins/pharmacology , Tetrazoles/chemical synthesis , Tetrazoles/therapeutic use , Viral Proteins/chemical synthesis , Viral Proteins/pharmacology , COVID-19 , Cell Division/drug effects , Drug Design , Drug Evaluation, Preclinical , Humans , Interleukin-1beta/metabolism , Macrophages/drug effects , Macrophages/metabolism , Tetrazoles/pharmacology , U937 Cells
20.
Autoimmun Rev ; 20(4): 102785, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1517045

ABSTRACT

The interleukin (IL) 1 family of cytokines is noteworthy to have pleiotropic functions in inflammation and acquired immunity. Over the last decades, several progresses have been made in understanding the function and regulation of the prototypical inflammatory cytokine (IL-1) in human diseases. IL-1α and IL-1ß deregulated signaling causes devastating diseases manifested by severe acute or chronic inflammation. In this review, we examine and compare the key aspects of IL-1α and IL-1ß biology and regulation and discuss their importance in the initiation and maintenance of inflammation that underlie the pathology of many human diseases. We also report the current and ongoing inhibitors of IL-1 signaling, targeting IL-1α, IL-1ß, their receptor or other molecular compounds as effective strategies to prevent or treat the onset and progression of various inflammatory disorders.


Subject(s)
Inflammation , Interleukin-1alpha , Adaptive Immunity , Humans , Interleukin-1beta , Signal Transduction
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