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1.
Ann Med ; 53(1): 181-188, 2021 12.
Article in English | MEDLINE | ID: covidwho-1575964

ABSTRACT

OBJECTIVE: To illustrate the effect of corticosteroids and heparin, respectively, on coronavirus disease 2019 (COVID-19) patients' CD8+ T cells and D-dimer. METHODS: In this retrospective cohort study involving 866 participants diagnosed with COVID-19, patients were grouped by severity. Generalized additive models were established to explore the time-course association of representative parameters of coagulation, inflammation and immunity. Segmented regression was performed to examine the influence of corticosteroids and heparin upon CD8+ T cell and D-dimer, respectively. RESULTS: There were 541 moderate, 169 severe and 156 critically ill patients involved in the study. Synchronous changes of levels of NLR, D-dimer and CD8+ T cell in critically ill patients were observed. Administration of methylprednisolone before 14 DFS compared with those after 14 DFS (ß = 0.154%, 95% CI=(0, 0.302), p=.048) or a dose lower than 40 mg per day compared with those equals to 40 mg per day (ß = 0.163%, 95% CI=(0.027, 0.295), p=.020) significantly increased the rising rate of CD8+ T cell in 14-56 DFS. CONCLUSIONS: The parameters of coagulation, inflammation and immunity were longitudinally correlated, and an early low-dose corticosteroid treatment accelerated the regaining of CD8+ T cell to help battle against SARS-Cov-2 in critical cases of COVID-19.


Subject(s)
CD8-Positive T-Lymphocytes/drug effects , COVID-19/drug therapy , Glucocorticoids/administration & dosage , Inflammation/drug therapy , Adult , Aged , Aged, 80 and over , Blood Coagulation/drug effects , Blood Coagulation/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/blood , COVID-19/diagnosis , COVID-19/immunology , Dose-Response Relationship, Drug , Female , Fibrin Fibrinogen Degradation Products/analysis , Fibrin Fibrinogen Degradation Products/immunology , Heparin/administration & dosage , Humans , Inflammation/blood , Inflammation/diagnosis , Inflammation/immunology , Linear Models , Longitudinal Studies , Lymphocyte Count , Male , Methylprednisolone/administration & dosage , Middle Aged , Models, Biological , Retrospective Studies , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification , Severity of Illness Index , Time Factors , Time-to-Treatment , Young Adult
2.
Int J Mol Sci ; 22(24)2021 Dec 15.
Article in English | MEDLINE | ID: covidwho-1572496

ABSTRACT

In humans, over-activation of innate immunity in response to viral or bacterial infections often causes severe illness and death. Furthermore, similar mechanisms related to innate immunity can cause pathogenesis and death in sepsis, massive trauma (including surgery and burns), ischemia/reperfusion, some toxic lesions, and viral infections including COVID-19. Based on the reviewed observations, we suggest that such severe outcomes may be manifestations of a controlled suicidal strategy protecting the entire population from the spread of pathogens and from dangerous pathologies rather than an aberrant hyperstimulation of defense responses. We argue that innate immunity may be involved in the implementation of an altruistic programmed death of an organism aimed at increasing the well-being of the whole community. We discuss possible ways to suppress this atavistic program by interfering with innate immunity and suggest that combating this program should be a major goal of future medicine.


Subject(s)
Altruism , Apoptosis/immunology , Immunity, Innate/immunology , Animals , COVID-19/immunology , Cell Death/immunology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/mortality , Humans , Inflammasomes/immunology , Inflammation/immunology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Signal Transduction/immunology
3.
Chem Biol Interact ; 352: 109776, 2022 Jan 25.
Article in English | MEDLINE | ID: covidwho-1568541

ABSTRACT

Boosting or suppressing our immune system represents an attractive adjunct in the treatment of infections including SARS-CoV-2, cancer, AIDS, malnutrition, age related problems and some inflammatory disorders. Thus, there has been a growing interest in exploring and developing novel drugs, natural or synthetic, that can manipulate our defence mechanism. Many of such studies, reported till date, have been designed to explore effect of the therapeutic on function of macrophages, being a key component in innate immune system. Indeed, RAW264.7, J774A.1, THP-1 and U937 cell lines act as ideal model systems for preliminary investigation and selection of dose for in vivo studies. Several bioassays have been standardized so far where many techniques require high throughput instruments, cost effective reagents and technical assistance that may hinder many scholars to perform a method demanding compilation of available protocols. In this review, we have taken an attempt for the first time to congregate commonly used in vitro immune-modulating techniques explaining their principles. The study detected that among about 40 different assays and more than 150 sets of primers, the methods of cell proliferation by MTT, phagocytosis by neutral red, NO detection by Griess reaction and estimation of expression of TLRs, COX-2, iNOS, TNF-α, IL-6 and IL-1ß by PCR have been the most widely used to screen the therapeutics under investigation.


Subject(s)
Immunity, Innate/immunology , Immunomodulation/immunology , Animals , Cell Line , Cell Line, Tumor , Cell Proliferation/physiology , Humans , Inflammation/immunology , Phagocytosis/immunology
4.
Chem Biol Interact ; 352: 109777, 2022 Jan 25.
Article in English | MEDLINE | ID: covidwho-1559106

ABSTRACT

OBJECTIVE: To determine the differences in the immune response against SARS-CoV-2 infection of patients based on sex and disease severity. METHODS: We used an analytical framework of 382 transcriptional modules and multi-omics analyses to discriminate COVID-19 patients based on sex and disease severity. RESULTS: Male and female patients overexpressed modules related to the innate immune response. The expression of modules related to the adaptive immune response showed lower enrichment levels in males than females. Inflammation modules showed ascending overexpression in male and female patients, while a higher level was observed in severe female patients. Moderate female patients demonstrated significant overexpression to interferon, cytolytic lymphocyte, T & B cells, and erythrocytes modules. Moderate female patients showed a higher adaptive immune response than males matched group. Pathways involved in metabolism dysregulation and Hippo signaling were upregulated in females than in male patients. Females and moderate cases showed higher levels of metabolic dysregulation. CONCLUSIONS: The immune landscape in COVID-19 patients was noticeably different between the sexes, and these differences may highlight disease vulnerability in males. This study suggested that certain treatments that increase or decrease the immune responses to SARS-CoV-2 might be necessary for male and female patients at certain disease stages.


Subject(s)
COVID-19/immunology , COVID-19/metabolism , Adaptive Immunity/immunology , Adult , Aged , COVID-19/pathology , Female , Humans , Immunity, Innate/immunology , Inflammation/immunology , Inflammation/metabolism , Inflammation/pathology , Lymphocytes/immunology , Lymphocytes/metabolism , Lymphocytes/pathology , Male , Middle Aged , SARS-CoV-2/immunology , Severity of Illness Index , Sex Characteristics
5.
Nutrients ; 13(12)2021 Nov 28.
Article in English | MEDLINE | ID: covidwho-1542691

ABSTRACT

This article focuses on how nutrition may help prevent and/or assist with recovery from the harmful effects of strenuous acute exercise and physical training (decreased immunity, organ injury, inflammation, oxidative stress, and fatigue), with a focus on nutritional supplements. First, the effects of ketogenic diets on metabolism and inflammation are considered. Second, the effects of various supplements on immune function are discussed, including antioxidant defense modulators (vitamin C, sulforaphane, taheebo), and inflammation reducers (colostrum and hyperimmunized milk). Third, how 3-hydroxy-3-methyl butyrate monohydrate (HMB) may offset muscle damage is reviewed. Fourth and finally, the relationship between exercise, nutrition and COVID-19 infection is briefly mentioned. While additional verification of the safety and efficacy of these supplements is still necessary, current evidence suggests that these supplements have potential applications for health promotion and disease prevention among athletes and more diverse populations.


Subject(s)
Antioxidants/therapeutic use , Athletes , Dietary Supplements , Exercise/immunology , Oxidative Stress , Physical Endurance , COVID-19/epidemiology , COVID-19/immunology , Humans , Inflammation/epidemiology , Inflammation/immunology , Oxidative Stress/drug effects , Oxidative Stress/immunology , Physical Endurance/drug effects , Physical Endurance/immunology , SARS-CoV-2/immunology , Sports Nutritional Sciences
6.
Front Immunol ; 12: 767981, 2021.
Article in English | MEDLINE | ID: covidwho-1528824

ABSTRACT

The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to constitute a serious public health threat worldwide. Protective antibody-mediated viral neutralization in response to SARS-CoV-2 infection has been firmly characterized. Where the effects of the antibody response are generally considered to be beneficial, an important biological question regarding potential negative outcomes of a SARS-CoV-2 antibody response has yet to be answered. We determined the distribution of IgG subclasses and complement activation levels in plasma from convalescent individuals using in-house developed ELISAs. The IgG response towards SARS-CoV-2 receptor-binding domain (RBD) after natural infection appeared to be mainly driven by IgG1 and IgG3 subclasses, which are the main ligands for C1q mediated classical complement pathway activation. The deposition of the complement components C4b, C3bc, and TCC as a consequence of SARS-CoV-2 specific antibodies were depending primarily on the SARS-CoV-2 RBD and significantly correlated with both IgG levels and disease severity, indicating that individuals with high levels of IgG and/or severe disease, might have a more prominent complement activation during viral infection. Finally, freshly isolated monocytes and a monocyte cell line (THP-1) were used to address the cellular mediated inflammatory response as a consequence of Fc-gamma receptor engagement by SARS-CoV-2 specific antibodies. Monocytic Fc gamma receptor charging resulted in a significant rise in the secretion of the pro-inflammatory cytokine TNF-α. Our results indicate that SARS-CoV-2 antibodies might drive significant inflammatory responses through the classical complement pathway and via cellular immune-complex activation that could have negative consequences during COVID-19 disease. We found that increased classical complement activation was highly associated to COVID-19 disease severity. The combination of antibody-mediated complement activation and subsequent cellular priming could constitute a significant risk of exacerbating COVID-19 severity.


Subject(s)
Antibodies, Viral/blood , COVID-19/immunology , Complement System Proteins/immunology , Immunoglobulin G/blood , SARS-CoV-2/immunology , COVID-19/blood , Complement Activation , Cytokines/immunology , Humans , Inflammation/immunology , Receptors, IgG/immunology , THP-1 Cells
7.
Expert Rev Anticancer Ther ; 21(12): 1371-1383, 2021 12.
Article in English | MEDLINE | ID: covidwho-1526146

ABSTRACT

INTRODUCTION: For the clinical treatment of cancer patients, coronavirus (SARS-CoV-2) can cause serious immune-related problems. Cancer patients, who experience immunosuppression due to the pathogenesis and severity of disease, may become more aggressive due to multiple factors such as age, comorbidities, and immunosuppression. In this pandemic era, COVID-19 causes lymphopenia, cancer cell awakening, inflammatory diseases, and a cytokine storm that worsens disease-related morbidity and prognosis. AREAS COVERED: We discuss all the risk factors of COVID-19 associated with cancer patients and propose new strategies to use antiviral and anticancer drugs for therapeutic purposes. We bring new drugs, cancers and COVID-19 treatment strategies together to address the immune system challenges faced by oncologists. EXPERT OPINION: The chronic inflammatory microenvironment caused by COVID-19 awakens dormant cancer cells through inflammation and autoimmune activation. Drug-related strategies to ensure that clinical treatment can reduce the susceptibility of cancer patients to COVID-19, and possible counter-measures to minimize the harm caused by the COVID-19 have been outlined. The response to the pandemic and recovery has been elaborated, which can provide information for long-term cancer treatment and speed up the optimization process.


Subject(s)
COVID-19/complications , Inflammation/drug therapy , Neoplasms/drug therapy , Antineoplastic Agents/administration & dosage , Antiviral Agents/administration & dosage , COVID-19/drug therapy , COVID-19/immunology , Humans , Inflammation/immunology , Inflammation/virology , Neoplasms/immunology , Neoplasms/virology , Prognosis , Risk Factors , Severity of Illness Index
8.
Front Immunol ; 12: 770066, 2021.
Article in English | MEDLINE | ID: covidwho-1518490

ABSTRACT

Acute inflammation is a critical host defense response during viral infection. When dysregulated, inflammation drives immunopathology and tissue damage. Excessive, damaging inflammation is a hallmark of both pandemic influenza A virus (IAV) infections and Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) infections. Chronic, low-grade inflammation is also a feature of obesity. In recent years, obesity has been recognized as a growing pandemic with significant mortality and associated costs. Obesity is also an independent risk factor for increased disease severity and death during both IAV and SARS-CoV-2 infection. This review focuses on the effect of obesity on the inflammatory response in the context of viral respiratory infections and how this leads to increased viral pathology. Here, we will review the fundamentals of inflammation, how it is initiated in IAV and SARS-CoV-2 infection and its link to disease severity. We will examine how obesity drives chronic inflammation and trained immunity and how these impact the immune response to IAV and SARS-CoV-2. Finally, we review both medical and non-medical interventions for obesity, how they impact on the inflammatory response and how they could be used to prevent disease severity in obese patients. As projections of global obesity numbers show no sign of slowing down, future pandemic preparedness will require us to consider the metabolic health of the population. Furthermore, if weight-loss alone is insufficient to reduce the risk of increased respiratory virus-related mortality, closer attention must be paid to a patient's history of health, and new therapeutic options identified.


Subject(s)
COVID-19/immunology , Inflammation/immunology , Influenza A virus , Influenza, Human/immunology , Obesity/immunology , SARS-CoV-2 , Animals , Humans , Severity of Illness Index
9.
Front Immunol ; 12: 738093, 2021.
Article in English | MEDLINE | ID: covidwho-1518484

ABSTRACT

Disease caused by SARS-CoV-2 coronavirus (COVID-19) led to significant morbidity and mortality worldwide. A systemic hyper-inflammation characterizes severe COVID-19 disease, often associated with acute respiratory distress syndrome (ARDS). Blood biomarkers capable of risk stratification are of great importance in effective triage and critical care of severe COVID-19 patients. Flow cytometry and next-generation sequencing were done on peripheral blood cells and urokinase-type plasminogen activator receptor (suPAR), and cytokines were measured from and mass spectrometry-based proteomics was done on plasma samples from an Indian cohort of COVID-19 patients. Publicly available single-cell RNA sequencing data were analyzed for validation of primary data. Statistical analyses were performed to validate risk stratification. We report here higher plasma abundance of suPAR, expressed by an abnormally expanded myeloid cell population, in severe COVID-19 patients with ARDS. The plasma suPAR level was found to be linked to a characteristic plasma proteome, associated with coagulation disorders and complement activation. Receiver operator characteristic curve analysis to predict mortality identified a cutoff value of suPAR at 1,996.809 pg/ml (odds ratio: 2.9286, 95% confidence interval 1.0427-8.2257). Lower-than-cutoff suPAR levels were associated with a differential expression of the immune transcriptome as well as favorable clinical outcomes, in terms of both survival benefit (hazard ratio: 0.3615, 95% confidence interval 0.1433-0.912) and faster disease remission in our patient cohort. Thus, we identified suPAR as a key pathogenic circulating molecule linking systemic hyperinflammation to the hypercoagulable state and stratifying clinical outcomes in severe COVID-19 patients with ARDS.


Subject(s)
COVID-19/blood , Receptors, Urokinase Plasminogen Activator/blood , SARS-CoV-2 , Adult , Aged , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/immunology , Blood Proteins/analysis , COVID-19/immunology , Cytokines/blood , Humans , Inflammation/blood , Inflammation/immunology , Middle Aged , Myeloid Cells/immunology , Proteome/analysis , Randomized Controlled Trials as Topic , Respiratory Distress Syndrome/blood , Respiratory Distress Syndrome/immunology , Severity of Illness Index , Young Adult
10.
Virol J ; 18(1): 211, 2021 10 29.
Article in English | MEDLINE | ID: covidwho-1486585

ABSTRACT

BACKGROUND: The SARS-CoV-2 virus is the causing agent of the Coronavirus disease 2019 (COVID-19) characterized by a huge pro-inflammatory response and coagulation disorders that may lead to for its severe forms, in organ failure or even death. As major players of thrombo-inflammation, platelets release large amounts of immunomodulatory molecules and regulate leukocyte and endothelial activity, which are both altered in COVID-19. Altogether, this makes platelets a very likely actor of the thrombo-inflammatory complications of COVID-19. Thus, we propose to identify a platelet inflammatory signature of severe COVID-19 specifically modulated throughout the course of the disease. METHODS: Luminex technology and enzyme-linked immunosorbent assay were used to assess plasma levels of platelet inflammatory markers in patients with severe acute respiratory syndrome coronavirus 2 infection on admission and for 14 days afterwards. RESULTS: In accordance with the observations of other teams, we evidence that the plasma levels of the platelet soluble (s)CD40L is significantly elevated in the early stages of the disease. Interestingly we observe that the plasma level of sCD40L decreases overtime while that of sCD62P increases significantly. CONCLUSIONS: Our data suggest that there is a platelet signature of inflammatory response to SARS-COv-2 infection which varies overtime and could serve as monitoring biomarkers of patient inflammatory state. CLINICAL TRIAL REGISTRATION NUMBER: 2020-A01100-39; title: Human Ab Response & immunoMONItoring of COVID-19 Patients, registration date: 05/25/2020; URL of the registry: https://clinicaltrials.gov/ct2/history/NCT04373200?V_5=View .


Subject(s)
Biomarkers/blood , Blood Platelets/immunology , COVID-19 , Inflammation , Adult , Aged , COVID-19/blood , COVID-19/immunology , Female , Humans , Inflammation/blood , Inflammation/immunology , Male , Middle Aged , Young Adult
11.
Front Immunol ; 12: 727861, 2021.
Article in English | MEDLINE | ID: covidwho-1477822

ABSTRACT

Inflammatory response is a host-protective mechanism against tissue injury or infections, but also has the potential to cause extensive immunopathology and tissue damage, as seen in many diseases, such as cardiovascular diseases, neurodegenerative diseases, metabolic syndrome and many other infectious diseases with public health concerns, such as Coronavirus Disease 2019 (COVID-19), if failure to resolve in a timely manner. Recent studies have uncovered a superfamily of endogenous chemical molecules that tend to resolve inflammatory responses and re-establish homeostasis without causing excessive damage to healthy cells and tissues. Among these, the monocyte chemoattractant protein-induced protein (MCPIP) family consisting of four members (MCPIP-1, -2, -3, and -4) has emerged as a group of evolutionarily conserved molecules participating in the resolution of inflammation. The focus of this review highlights the biological functions of MCPIP-1 (also known as Regnase-1), the best-studied member of this family, in the resolution of inflammatory response. As outlined in this review, MCPIP-1 acts on specific signaling pathways, in particular NFκB, to blunt production of inflammatory mediators, while also acts as an endonuclease controlling the stability of mRNA and microRNA (miRNA), leading to the resolution of inflammation, clearance of virus and dead cells, and promotion of tissue regeneration via its pleiotropic effects. Evidence from transgenic and knock-out mouse models revealed an involvement of MCPIP-1 expression in immune functions and in the physiology of the cardiovascular system, indicating that MCPIP-1 is a key endogenous molecule that governs normal resolution of acute inflammation and infection. In this review, we also discuss the current evidence underlying the roles of other members of the MCPIP family in the regulation of inflammatory processes. Further understanding of the proteins from this family will provide new insights into the identification of novel targets for both host effectors and microbial factors and will lead to new therapeutic treatments for infections and other inflammatory diseases.


Subject(s)
Gene Expression Regulation/genetics , Inflammation Mediators/metabolism , Inflammation/immunology , Ribonucleases/immunology , SARS-CoV-2/immunology , Transcription Factors/immunology , Animals , Apoptosis/genetics , COVID-19/immunology , Humans , Inflammation/pathology , Mice , NF-kappa B/metabolism , RNA Processing, Post-Transcriptional/genetics , Transcriptional Activation/immunology , Ubiquitination
12.
Nat Immunol ; 22(11): 1416-1427, 2021 11.
Article in English | MEDLINE | ID: covidwho-1475314

ABSTRACT

Ubiquitin-like protein ISG15 (interferon-stimulated gene 15) (ISG15) is a ubiquitin-like modifier induced during infections and involved in host defense mechanisms. Not surprisingly, many viruses encode deISGylating activities to antagonize its effect. Here we show that infection by Zika, SARS-CoV-2 and influenza viruses induce ISG15-modifying enzymes. While influenza and Zika viruses induce ISGylation, SARS-CoV-2 triggers deISGylation instead to generate free ISG15. The ratio of free versus conjugated ISG15 driven by the papain-like protease (PLpro) enzyme of SARS-CoV-2 correlates with macrophage polarization toward a pro-inflammatory phenotype and attenuated antigen presentation. In vitro characterization of purified wild-type and mutant PLpro revealed its strong deISGylating over deubiquitylating activity. Quantitative proteomic analyses of PLpro substrates and secretome from SARS-CoV-2-infected macrophages revealed several glycolytic enzymes previously implicated in the expression of inflammatory genes and pro-inflammatory cytokines, respectively. Collectively, our results indicate that altered free versus conjugated ISG15 dysregulates macrophage responses and probably contributes to the cytokine storms triggered by SARS-CoV-2.


Subject(s)
COVID-19/immunology , Cytokines/metabolism , Inflammation/immunology , Macrophages/immunology , SARS-CoV-2/physiology , Ubiquitins/metabolism , Cell Differentiation , Coronavirus Papain-Like Proteases/metabolism , Cytokines/genetics , Gene Knockdown Techniques , HeLa Cells , Humans , Immune Evasion , Immunity, Innate , Influenza A virus/physiology , Influenza, Human/immunology , Pluripotent Stem Cells/cytology , Ubiquitination , Ubiquitins/genetics , Zika Virus/physiology , Zika Virus Infection/immunology
13.
J Clin Invest ; 131(20)2021 10 15.
Article in English | MEDLINE | ID: covidwho-1470549

ABSTRACT

Multisystem inflammatory syndrome in children (MIS-C) manifests as a severe and uncontrolled inflammatory response with multiorgan involvement, occurring weeks after SARS-CoV-2 infection. Here, we utilized proteomics, RNA sequencing, autoantibody arrays, and B cell receptor (BCR) repertoire analysis to characterize MIS-C immunopathogenesis and identify factors contributing to severe manifestations and intensive care unit admission. Inflammation markers, humoral immune responses, neutrophil activation, and complement and coagulation pathways were highly enriched in MIS-C patient serum, with a more hyperinflammatory profile in severe than in mild MIS-C cases. We identified a strong autoimmune signature in MIS-C, with autoantibodies targeted to both ubiquitously expressed and tissue-specific antigens, suggesting autoantigen release and excessive antigenic drive may result from systemic tissue damage. We further identified a cluster of patients with enhanced neutrophil responses as well as high anti-Spike IgG and autoantibody titers. BCR sequencing of these patients identified a strong imprint of antigenic drive with substantial BCR sequence connectivity and usage of autoimmunity-associated immunoglobulin heavy chain variable region (IGHV) genes. This cluster was linked to a TRBV11-2 expanded T cell receptor (TCR) repertoire, consistent with previous studies indicating a superantigen-driven pathogenic process. Overall, we identify a combination of pathogenic pathways that culminate in MIS-C and may inform treatment.


Subject(s)
Autoimmunity , COVID-19/complications , Systemic Inflammatory Response Syndrome/immunology , Adaptive Immunity , Adolescent , Biomarkers/metabolism , COVID-19/genetics , COVID-19/immunology , COVID-19/metabolism , Case-Control Studies , Child , Child, Preschool , Cohort Studies , Cytokine Release Syndrome/immunology , Female , Humans , Infant , Inflammation/immunology , Male , Mucocutaneous Lymph Node Syndrome/genetics , Mucocutaneous Lymph Node Syndrome/immunology , Mucocutaneous Lymph Node Syndrome/metabolism , Neutrophil Activation , Proteomics , RNA-Seq , Receptors, Antigen, B-Cell/genetics , Severity of Illness Index , Systemic Inflammatory Response Syndrome/genetics , Systemic Inflammatory Response Syndrome/metabolism
14.
Med Sci Monit ; 26: e922281, 2020 Mar 31.
Article in English | MEDLINE | ID: covidwho-1453382

ABSTRACT

BACKGROUND Acute respiratory distress syndrome (ARDS) is a sudden and serious disease with increasing morbidity and mortality rates. Phosphodiesterase 4 (PDE4) is a novel target for inflammatory disease, and ibudilast (IBU), a PDE4 inhibitor, inhibits inflammatory response. Our study investigated the effect of IBU on the pathogenesis of neonatal ARDS and the underlying mechanism related to it. MATERIAL AND METHODS Western blotting was performed to analyze the expression levels of PDE4, CXCR4, SDF-1, CXCR5, CXCL1, inflammatory cytokines, and proteins related to cell apoptosis. Hematoxylin-eosin staining was performed to observe the pathological morphology of lung tissue. Pulmonary edema score was used to assess the degree of lung water accumulation after pulmonary injury. Enzyme-linked immunosorbent assay (ELISA) was used to assess levels of inflammatory factors (TNF-alpha, IL-1ß, IL-6, and MCP-1) in serum. TUNEL assay was used to detect apoptotic cells. RESULTS Increased expression of PDE4 was observed in an LPS-induced neonatal ARDS mouse model, and IBU ameliorated LPS-induced pathological manifestations and pulmonary edema in lung tissue. In addition, IBU attenuated the secretion of inflammatory cytokines by inactivating the chemokine axis in the LPS-induced neonatal ARDS mouse model. Finally, IBU significantly reduced LPS-induced cell apoptosis in lung tissue. CONCLUSIONS IBU, a PDE4 inhibitor, protected against ARDS by interfering with pulmonary inflammation and apoptosis. Our findings provide a novel and promising strategy to regulate pulmonary inflammation in ARDS.


Subject(s)
Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Inflammation/drug therapy , Phosphodiesterase 4 Inhibitors/pharmacology , Pyridines/pharmacology , Respiratory Distress Syndrome, Newborn/drug therapy , Animals , Animals, Newborn , Apoptosis/drug effects , Apoptosis/immunology , Bronchoalveolar Lavage Fluid , Disease Models, Animal , Humans , Inflammation/diagnosis , Inflammation/immunology , Inflammation/pathology , Injections, Intraperitoneal , Lipopolysaccharides/immunology , Lung/drug effects , Lung/immunology , Lung/pathology , Mice , Phosphodiesterase 4 Inhibitors/therapeutic use , Pyridines/therapeutic use , Respiratory Distress Syndrome, Newborn/diagnosis , Respiratory Distress Syndrome, Newborn/immunology , Respiratory Distress Syndrome, Newborn/pathology , Signal Transduction/drug effects , Signal Transduction/immunology
15.
Front Immunol ; 12: 709759, 2021.
Article in English | MEDLINE | ID: covidwho-1450807

ABSTRACT

The clinical features of SARS-CoV-2 infection range from asymptomatic to severe disease with life-threatening complications. Understanding the persistence of immune responses in asymptomatic individuals merit special attention because of their importance in controlling the spread of the infections. We here studied the antibody and T cell responses, and a wide range of inflammation markers, in 56 SARS-CoV-2 antibody-positive individuals, identified by a population screen after the first wave of SARS-CoV-2 infection. These, mostly asymptomatic individuals, were reanalyzed 7-8 months after their infection together with 115 age-matched seronegative controls. We found that 7-8 months after the infection their antibodies to SARS-CoV-2 Nucleocapsid (N) protein declined whereas we found no decrease in the antibodies to Spike receptor-binding domain (S-RBD) when compared to the findings at seropositivity identification. In contrast to antibodies to N protein, the antibodies to S-RBD correlated with the viral neutralization capacity and with CD4+ T cell responses as measured by antigen-specific upregulation of CD137 and CD69 markers. Unexpectedly we found the asymptomatic antibody-positive individuals to have increased serum levels of S100A12, TGF-alpha, IL18, and OSM, the markers of activated macrophages-monocytes, suggesting long-term persistent inflammatory effect associated with the viral infection in asymptomatic individuals. Our results support the evidence for the long-term persistence of the inflammation process and the need for post-infection clinical monitoring of SARS-CoV-2 infected asymptomatic individuals.


Subject(s)
Antibodies, Viral/blood , Asymptomatic Infections , CD4-Positive T-Lymphocytes/immunology , COVID-19/pathology , Inflammation Mediators/blood , SARS-CoV-2/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , CD4 Lymphocyte Count , Coronavirus Nucleocapsid Proteins/immunology , Humans , Inflammation/immunology , Interleukin-18/blood , Macrophages/immunology , Monocytes/immunology , Oncostatin M/blood , Phosphoproteins/immunology , Protein Domains/immunology , S100A12 Protein/blood , Spike Glycoprotein, Coronavirus/immunology , Transforming Growth Factor alpha/blood
16.
Clin Appl Thromb Hemost ; 27: 10760296211045902, 2021.
Article in English | MEDLINE | ID: covidwho-1443743

ABSTRACT

INTRODUCTION: Diabetes is the most common of comorbidity in patients with SARS-COV-2 pneumonia. Coagulation abnormalities with D-dimer levels are increased in this disease. OBJECTIFS: We aimed to compare the levels of D-dimer in diabetic and non-diabetic patients with COVID 19. A link between D-dimer and mortality has also been established. MATERIALS: A retrospective study was carried out at the University Hospital Center of Oujda (Morocco) from November 01st to December 01st, 2020. Our study population was divided into two groups: a diabetic group and a second group without diabetes to compare clinical and biological characteristics between the two groups. In addition, the receiver operator characteristic curve was used to assess the optimal D-dimer cut-off point for predicting mortality in diabetics. RESULTS: 201 confirmed-COVID-19-patients were included in the final analysis. The median age was 64 (IQR 56-73), and 56% were male. Our study found that D-dimer levels were statistically higher in diabetic patients compared to non-diabetic patients. (1745 vs 845 respectively, P = 0001). D-dimer level > 2885 ng/mL was a significant predictor of mortality in diabetic patients with a sensitivity of 71,4% and a specificity of 70,7%. CONCLUSION: Our study found that diabetics with COVID-19 are likely to develop hypercoagulation with a poor prognosis.


Subject(s)
COVID-19/blood , Diabetes Mellitus/blood , Fibrin Fibrinogen Degradation Products/analysis , SARS-CoV-2 , Thrombophilia/blood , Aged , Area Under Curve , Biomarkers , C-Reactive Protein/analysis , COVID-19/complications , COVID-19/epidemiology , Comorbidity , Diabetes Complications/blood , Diabetes Complications/epidemiology , Diabetes Mellitus/epidemiology , Female , Hospital Mortality , Humans , Hypertension/epidemiology , Inflammation/immunology , Kaplan-Meier Estimate , Male , Middle Aged , Oxidative Stress , Prognosis , ROC Curve , Retrospective Studies , Risk Factors , Thrombophilia/etiology , Thrombophilia/immunology
17.
Immunity ; 54(11): 2650-2669.e14, 2021 11 09.
Article in English | MEDLINE | ID: covidwho-1442406

ABSTRACT

Longitudinal analyses of the innate immune system, including the earliest time points, are essential to understand the immunopathogenesis and clinical course of coronavirus disease (COVID-19). Here, we performed a detailed characterization of natural killer (NK) cells in 205 patients (403 samples; days 2 to 41 after symptom onset) from four independent cohorts using single-cell transcriptomics and proteomics together with functional studies. We found elevated interferon (IFN)-α plasma levels in early severe COVD-19 alongside increased NK cell expression of IFN-stimulated genes (ISGs) and genes involved in IFN-α signaling, while upregulation of tumor necrosis factor (TNF)-induced genes was observed in moderate diseases. NK cells exert anti-SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) activity but are functionally impaired in severe COVID-19. Further, NK cell dysfunction may be relevant for the development of fibrotic lung disease in severe COVID-19, as NK cells exhibited impaired anti-fibrotic activity. Our study indicates preferential IFN-α and TNF responses in severe and moderate COVID-19, respectively, and associates a prolonged IFN-α-induced NK cell response with poorer disease outcome.


Subject(s)
COVID-19/immunology , Interferon-alpha/immunology , Killer Cells, Natural/immunology , SARS-CoV-2/immunology , Tumor Necrosis Factor-alpha/metabolism , Base Sequence , Humans , Immunity, Innate/immunology , Inflammation/immunology , Interferon-alpha/blood , Pulmonary Fibrosis/pathology , RNA-Seq , Severity of Illness Index , Transcriptome/genetics , United Kingdom , United States
18.
Naunyn Schmiedebergs Arch Pharmacol ; 394(11): 2187-2195, 2021 11.
Article in English | MEDLINE | ID: covidwho-1442084

ABSTRACT

Millions of people around the world are involved with COVID-19 due to infection with SARS-CoV-2. Virological features of SARS-CoV-2, including its genomic sequence, have been identified but the mechanisms governing COVID-19 immunopathogenesis have remained uncertain. miR-223 is a hematopoietic cell-derived miRNA that is implicated in regulating monocyte-macrophage differentiation, neutrophil recruitment, and pro-inflammatory responses. The miR-223 controls inflammation by targeting a variety of factors, including TRAF6, IKKα, HSP-70, FOXO1, TLR4, PI3K/AKT, PARP-1, HDAC2, ITGB3, CXCL2, CCL3, IL-6, IFN-I, STMN1, IL-1ß, IL-18, Caspase-1, NF-κB, and NLRP3. The key role of miR-223 in regulating the inflammatory process and its antioxidant and antiviral role can suggest this miRNA as a potential regulatory factor in the process of COVID-19 immunopathogenesis.


Subject(s)
COVID-19/genetics , COVID-19/pathology , Inflammasomes/genetics , Inflammation/genetics , Inflammation/pathology , MicroRNAs/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Animals , COVID-19/immunology , Humans , Inflammasomes/immunology , Inflammation/immunology
19.
Int J Immunopathol Pharmacol ; 35: 20587384211048026, 2021.
Article in English | MEDLINE | ID: covidwho-1440891

ABSTRACT

COVID-19 is a highly heterogeneous and complex medical disorder; indeed, severe COVID-19 is probably amongst the most complex of medical conditions known to medical science. While enormous strides have been made in understanding the molecular pathways involved in patients infected with coronaviruses an overarching and comprehensive understanding of the pathogenesis of COVID-19 is lacking. Such an understanding is essential in the formulation of effective prophylactic and treatment strategies. Based on clinical, proteomic, and genomic studies as well as autopsy data severe COVID-19 disease can be considered to be the connection of three basic pathologic processes, namely a pulmonary macrophage activation syndrome with uncontrolled inflammation, a complement-mediated endothelialitis together with a procoagulant state with a thrombotic microangiopathy. In addition, platelet activation with the release of serotonin and the activation and degranulation of mast cells contributes to the hyper-inflammatory state. Auto-antibodies have been demonstrated in a large number of hospitalized patients which adds to the end-organ damage and pro-thrombotic state. This paper provides a clinical overview of the major pathogenetic mechanism leading to severe COVID-19 disease.


Subject(s)
COVID-19/virology , SARS-CoV-2/pathogenicity , COVID-19/blood , COVID-19/immunology , COVID-19/physiopathology , Complement Activation , Complement System Proteins/metabolism , Cytokines/blood , Disease Progression , Host-Pathogen Interactions , Humans , Inflammation/blood , Inflammation/immunology , Inflammation/physiopathology , Inflammation/virology , Inflammation Mediators/blood , Macrophage Activation Syndrome/blood , Macrophage Activation Syndrome/immunology , Macrophage Activation Syndrome/physiopathology , Macrophage Activation Syndrome/virology , Platelet Activation , SARS-CoV-2/immunology , Serotonin/blood , Severity of Illness Index , Thrombotic Microangiopathies/blood , Thrombotic Microangiopathies/immunology , Thrombotic Microangiopathies/physiopathology , Thrombotic Microangiopathies/virology
20.
Molecules ; 26(17)2021 Sep 01.
Article in English | MEDLINE | ID: covidwho-1436074

ABSTRACT

Nutraceutical, a term derived from 'nutrition' and 'pharmaceutical', refers to any product isolated from herbs, nutrients, specific diets, processed foods, and beverages used not only for nutritional but also for medicinal purposes [...].


Subject(s)
Communicable Diseases/immunology , Dietary Supplements , Gastrointestinal Diseases/immunology , Inflammation/immunology , Neoplasms/immunology , Nutritional Status/immunology , Humans
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