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1.
Cell Transplant ; 30: 9636897211054481, 2021.
Article in English | MEDLINE | ID: covidwho-1511642

ABSTRACT

Biological and cellular interleukin-6 (IL-6)-related therapies have been used to treat severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure, which prompted further exploration of the role of IL-6 in human umbilical cord mesenchymal stem cell (hUCMSC) therapy. Peripheral blood mononuclear cells (PBMCs) were responders cocultured with hUCMSCs or exogenous IL-6. A PBMC suppression assay was used to analyze the anti-inflammatory effects via MTT assay. The IL-6 concentration in the supernatant was measured using ELISA. The correlation between the anti-inflammatory effect of hUCMSCs and IL-6 levels and the relevant roles of IL-6 and IL-6 mRNA expression was analyzed using the MetaCore functional network constructed from gene microarray data. The location of IL-6 and IL-6 receptor (IL-6R) expression was further evaluated. We reported that hUCMSCs did not initially exert any inhibitory effect on PHA-stimulated proliferation; however, a potent inhibitory effect on PHA-stimulated proliferation was observed, and the IL-6 concentration reached approximately 1000 ng/mL after 72 hours. Exogenous 1000 ng/mL IL-6 inhibited PHA-stimulated inflammation but less so than hUCMSCs. The inhibitory effects of hUCMSCs on PHA-stimulated PBMCs disappeared after adding an IL-6 neutralizing antibody or pretreatment with tocilizumab (TCZ), an IL-6R antagonist. hUCMSCs exert excellent anti-inflammatory effects by inducing higher IL-6 levels, which is different from TCZ. High concentration of IL-6 cytokine secretion plays an important role in the anti-inflammatory effect of hUCMSC therapy. Initial hUCMSC therapy, followed by TCZ, seems to optimize the therapeutic potential to treat COVID-19-related acute respiratory distress syndrome (ARDS).


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/complications , Interleukin-6/biosynthesis , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/metabolism , Respiratory Distress Syndrome/therapy , SARS-CoV-2 , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Neutralizing/immunology , Cells, Cultured , Coculture Techniques , Combined Modality Therapy , DNA, Complementary/genetics , Gene Expression Regulation/drug effects , Humans , Inflammation , Interleukin-6/genetics , Interleukin-6/pharmacology , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Lymphocyte Activation/drug effects , Phytohemagglutinins/pharmacology , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Receptors, Interleukin-6/antagonists & inhibitors , Receptors, Interleukin-6/biosynthesis , Receptors, Interleukin-6/genetics , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/etiology , Umbilical Cord/cytology
2.
Sci Rep ; 11(1): 20638, 2021 10 19.
Article in English | MEDLINE | ID: covidwho-1475483

ABSTRACT

The COVID-19 pandemic is an unprecedented threat to humanity that has provoked global health concerns. Since the etiopathogenesis of this illness is not fully characterized, the prognostic factors enabling treatment decisions have not been well documented. Accurately predicting the progression of the disease would aid in appropriate patient categorization and thus help determine the best treatment option. Here, we have introduced a proteomic approach utilizing data-independent acquisition mass spectrometry (DIA-MS) to identify the serum proteins that are closely associated with COVID-19 prognosis. Twenty-seven proteins were differentially expressed between severely ill COVID-19 patients with an adverse or favorable prognosis. Ingenuity Pathway Analysis revealed that 15 of the 27 proteins might be regulated by cytokine signaling relevant to interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF), and their differential expression was implicated in the systemic inflammatory response and in cardiovascular disorders. We further evaluated practical predictors of the clinical prognosis of severe COVID-19 patients. Subsequent ELISA assays revealed that CHI3L1 and IGFALS may serve as highly sensitive prognostic markers. Our findings can help formulate a diagnostic approach for accurately identifying COVID-19 patients with severe disease and for providing appropriate treatment based on their predicted prognosis.


Subject(s)
Biomarkers/blood , COVID-19 Serological Testing/methods , COVID-19/blood , Gene Expression Profiling , Proteomics/methods , Chitinase-3-Like Protein 1/metabolism , Enzyme-Linked Immunosorbent Assay , Gas Chromatography-Mass Spectrometry , Gene Expression Regulation , Humans , Inflammation , Interleukin-1beta/biosynthesis , Interleukin-6/biosynthesis , Prognosis , SARS-CoV-2 , Tumor Necrosis Factor-alpha/biosynthesis , Virus Diseases
3.
Brief Bioinform ; 22(2): 936-945, 2021 03 22.
Article in English | MEDLINE | ID: covidwho-1352108

ABSTRACT

Interleukin 6 (IL-6) is a pro-inflammatory cytokine that stimulates acute phase responses, hematopoiesis and specific immune reactions. Recently, it was found that the IL-6 plays a vital role in the progression of COVID-19, which is responsible for the high mortality rate. In order to facilitate the scientific community to fight against COVID-19, we have developed a method for predicting IL-6 inducing peptides/epitopes. The models were trained and tested on experimentally validated 365 IL-6 inducing and 2991 non-inducing peptides extracted from the immune epitope database. Initially, 9149 features of each peptide were computed using Pfeature, which were reduced to 186 features using the SVC-L1 technique. These features were ranked based on their classification ability, and the top 10 features were used for developing prediction models. A wide range of machine learning techniques has been deployed to develop models. Random Forest-based model achieves a maximum AUROC of 0.84 and 0.83 on training and independent validation dataset, respectively. We have also identified IL-6 inducing peptides in different proteins of SARS-CoV-2, using our best models to design vaccine against COVID-19. A web server named as IL-6Pred and a standalone package has been developed for predicting, designing and screening of IL-6 inducing peptides (https://webs.iiitd.edu.in/raghava/il6pred/).


Subject(s)
COVID-19/physiopathology , Computer Simulation , Interleukin-6/biosynthesis , Peptides/metabolism , COVID-19/virology , Databases, Protein , Datasets as Topic , Humans , Interleukin-6/physiology , Machine Learning , SARS-CoV-2/isolation & purification
4.
Front Immunol ; 12: 685344, 2021.
Article in English | MEDLINE | ID: covidwho-1295638

ABSTRACT

Vaccination is the best prophylaxis for the prevention of infectious diseases, including coronavirus disease 2019. However, the efficacy of vaccines and onset of adverse reactions vary among individuals. Circulating extracellular vesicles (EVs) regulate the immune responses after vaccination by delivering microRNAs (miRNAs) to myeloid and lymphoid cells. Among these, miR-192 levels in serum EVs increase with aging, in an IL-6-dependent manner, reducing excessive IL-6 expression in aged mice, creating a negative feedback loop. Excessive IL-6 expression reduces vaccination efficacy in aged mice, while EV miR-192 improves efficacy in these aged mice as well, making this miRNA an interesting focus of study. miR-21 levels in serum EVs also increase with aging, and regulates the expression of IL-12 required for Th1 responses; therefore, EV miR-21 is expected to regulate vaccine efficacy. miR-451a, another important miRNA, is abundant in serum EVs and controls the expression of cytokines, such as type I interferon and IL-6. However, levels differ among individuals and correlate with local inflammatory symptoms experienced after a seasonal flu vaccination. These findings suggest the importance of EV miRNAs as a tool to improve vaccine efficacy and also as biomarkers to predict the immune response and adverse reactions after vaccinations.


Subject(s)
Extracellular Vesicles/metabolism , Interferon Type I/immunology , Interleukin-6/immunology , MicroRNAs/blood , Aging/blood , Aging/immunology , COVID-19/immunology , COVID-19/prevention & control , COVID-19 Vaccines/immunology , Humans , Interferon Type I/biosynthesis , Interleukin-12 Subunit p35/biosynthesis , Interleukin-12 Subunit p35/immunology , Interleukin-6/biosynthesis , MicroRNAs/genetics , SARS-CoV-2/immunology , Th1 Cells/immunology , Vaccination
6.
Int J Radiat Oncol Biol Phys ; 110(5): 1283-1294, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1129036

ABSTRACT

PURPOSE: Severe pneumonia and acute respiratory distress syndrome (ARDS) have been described in patients with severe coronavirus disease 2019 (COVID-19). Recently, early clinical data reported the feasibility of low doses of radiation therapy (RT) in the treatment of ARDS in patients with severe COVID-19. However, the involved mechanisms remained unknown. METHODS AND MATERIALS: Here, we used airways-instilled lipopolysaccharide (LPS) and influenza virus (H1N1) as murine models of pneumonia, and toll-like receptor (TLR)-3 stimulation in human lung macrophages. RESULTS: Low doses of RT (0.5-1 Gray) decreased LPS-induced pneumonia, and increased the percentage of nerve- and airway-associated macrophages producing interleukin (IL) 10. During H1N1 viral infection, we observed decreased lung tissue damage and immune cell infiltration in irradiated animals. Low doses of RT increased IL-10 production by infiltrating immune cells into the lung. Irradiation of TLR-3 ligand-stimulated human lung macrophages ex vivo increased IL-10 secretion and decreased interferon γ production in the culture supernatant. The percentage of human lung macrophages producing IL-6 was also decreased. CONCLUSIONS: Our data highlight a mechanism by which low doses of RT regulate lung inflammation and skew lung macrophages toward an anti-inflammatory profile. These data provide a preclinical mechanistic support to clinical trials evaluating low doses of RT, such as COVID-19-induced ARDS.


Subject(s)
Epithelial Cells/radiation effects , Influenza A Virus, H1N1 Subtype , Interleukin-10/biosynthesis , Macrophages/radiation effects , Pneumonia, Viral/radiotherapy , Respiratory Distress Syndrome/radiotherapy , Animals , Anti-Inflammatory Agents/pharmacology , COVID-19/complications , Dexamethasone/pharmacology , Disease Models, Animal , Epithelial Cells/drug effects , Epithelial Cells/immunology , Epithelial Cells/metabolism , Female , Flow Cytometry , Humans , Influenza A Virus, H1N1 Subtype/radiation effects , Interferon-gamma/biosynthesis , Interleukin-6/biosynthesis , Lipopolysaccharides , Lung/cytology , Lung/pathology , Lung/radiation effects , Macrophages/drug effects , Macrophages/immunology , Macrophages/metabolism , Mice , Mice, Inbred C57BL , Pneumonia, Viral/etiology , Pneumonia, Viral/prevention & control , Poly I-C , Radiotherapy Dosage , Respiratory Distress Syndrome/etiology , Toll-Like Receptor 3 , Viral Load/radiation effects
7.
Science ; 371(6532)2021 02 26.
Article in English | MEDLINE | ID: covidwho-1066801

ABSTRACT

Immunoglobulin G (IgG) antibodies are crucial for protection against invading pathogens. A highly conserved N-linked glycan within the IgG-Fc tail, which is essential for IgG function, shows variable composition in humans. Afucosylated IgG variants are already used in anticancer therapeutic antibodies for their increased activity through Fc receptors (FcγRIIIa). Here, we report that afucosylated IgG (approximately 6% of total IgG in humans) are specifically formed against enveloped viruses but generally not against other antigens. This mediates stronger FcγRIIIa responses but also amplifies brewing cytokine storms and immune-mediated pathologies. Critically ill COVID-19 patients, but not those with mild symptoms, had high concentrations of afucosylated IgG antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), amplifying proinflammatory cytokine release and acute phase responses. Thus, antibody glycosylation plays a critical role in immune responses to enveloped viruses, including COVID-19.


Subject(s)
Antibodies, Viral/immunology , COVID-19/immunology , Immunoglobulin G/immunology , SARS-CoV-2/immunology , Adult , Aged , Antibodies, Viral/blood , Antibodies, Viral/chemistry , COVID-19/physiopathology , Cells, Cultured , Critical Illness , Cytomegalovirus/immunology , Female , Fucose/analysis , Glycosylation , HIV/immunology , Hepatitis B Vaccines/immunology , Humans , Immunoglobulin Fc Fragments/chemistry , Immunoglobulin Fc Fragments/immunology , Immunoglobulin G/blood , Immunoglobulin G/chemistry , Inflammation , Interleukin-6/biosynthesis , Interleukin-6/immunology , Macrophages/immunology , Male , Middle Aged , Parvovirus B19, Human/immunology , Severity of Illness Index , Spike Glycoprotein, Coronavirus/immunology , Vaccines, Subunit/immunology , Young Adult
8.
Expert Rev Mol Diagn ; 20(11): 1087-1097, 2020 11.
Article in English | MEDLINE | ID: covidwho-800633

ABSTRACT

INTRODUCTION: Coronavirus disease (COVID-19) can trigger a cytokine response storm (CRS) that is associated with high mortality but for which the underlying pathophysiology and diagnostics are not yet well characterized. This review provides an overview of the underlying immune profile of COVID-19-related CRS as well as laboratory markers for acute diagnosis and chronic follow-up of patients with SARS-CoV-2 and CRS. AREAS COVERED: Innate and acquired immune profiles in COVID-19-CRS, RNA-detection methods for SARS-CoV-2 in the setting of CRS including factors that affect assay performance, serology for SARS-CoV-2 in the setting of CRS, and other biomarkers for COVID-19 will be discussed. EXPERT OPINION: Studies support the implication of CRS in the pathogenesis, clinical severity and outcome of COVID-19 through the production of multiple inflammatory cytokines and chemokines from activated innate and adaptive immune cells. Although these inflammatory molecules, including IL-6, IL-2 R, IL-10, IP-10 and MCP-1, often correlate with disease severity as possible biomarkers, the pathogenic contributions of individual molecules and the therapeutic benefits of targeting them are yet to be demonstrated. Detection of SARS-CoV-2 RNA is the gold standard method for diagnosis of COVID-19 in the context of CRS but assay performance varies and is susceptible to false-negative results even as patients clinically deteriorate due to decreased viral shedding in the setting of CRS. Biomarkers including CRP, ferritin, D-dimer and procalcitonin may provide early clues about progression to CRS and help identify thrombotic and infectious complications of COVID-19.


Subject(s)
Biomarkers/blood , COVID-19/blood , Cytokine Release Syndrome/blood , Cytokines/blood , Adaptive Immunity/immunology , COVID-19/diagnosis , COVID-19/immunology , COVID-19/virology , Chemokine CCL2/biosynthesis , Chemokine CCL2/immunology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/virology , Cytokines/biosynthesis , Cytokines/immunology , Humans , Immunity, Innate/immunology , Interleukin-10/biosynthesis , Interleukin-10/immunology , Interleukin-6/biosynthesis , Interleukin-6/immunology , Pandemics , Receptors, Interleukin-2/biosynthesis , Receptors, Interleukin-2/immunology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Severity of Illness Index
9.
Platelets ; 31(8): 1085-1089, 2020 Nov 16.
Article in English | MEDLINE | ID: covidwho-733448

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a global public health emergency with many clinical facets, and new knowledge about its pathogenetic mechanisms is deemed necessary; among these, there are certainly coagulation disorders. In the history of medicine, autopsies and tissue sampling have played a fundamental role in order to understand the pathogenesis of emerging diseases, including infectious ones; compared to the past, histopathology can be now expanded by innovative techniques and modern technologies. For the first time in worldwide literature, we provide a detailed postmortem and biopsy report on the marked increase, up to 1 order of magnitude, of naked megakaryocyte nuclei in the bone marrow and lungs from serious COVID-19 patients. Most likely related to high interleukin-6 serum levels stimulating megakaryocytopoiesis, this phenomenon concurs to explain well the pulmonary abnormal immunothrombosis in these critically ill patients, all without molecular or electron microscopy signs of megakaryocyte infection.


Subject(s)
Betacoronavirus/pathogenicity , Bone Marrow/pathology , Coronavirus Infections/pathology , Cytokine Release Syndrome/pathology , Disseminated Intravascular Coagulation/pathology , Lung/pathology , Pneumonia, Viral/pathology , Thrombosis/pathology , Adult , Aged , Autopsy , Betacoronavirus/immunology , Bone Marrow/immunology , Bone Marrow/virology , COVID-19 , Cell Nucleus/immunology , Cell Nucleus/pathology , Cell Nucleus/virology , Coronavirus Infections/complications , Coronavirus Infections/immunology , Coronavirus Infections/virology , Critical Illness , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/virology , Disseminated Intravascular Coagulation/complications , Disseminated Intravascular Coagulation/immunology , Disseminated Intravascular Coagulation/virology , Fatal Outcome , Host-Pathogen Interactions/immunology , Humans , Interleukin-6/biosynthesis , Interleukin-6/immunology , Lung/immunology , Lung/virology , Male , Megakaryocytes/immunology , Megakaryocytes/pathology , Megakaryocytes/virology , Middle Aged , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , SARS-CoV-2 , Severity of Illness Index , Thrombopoiesis/immunology , Thrombosis/complications , Thrombosis/immunology , Thrombosis/virology
10.
J Immunol ; 205(5): 1198-1206, 2020 09 01.
Article in English | MEDLINE | ID: covidwho-654195

ABSTRACT

Fever in infections correlates with inflammation, macrophage infiltration into the affected organ, macrophage activation, and release of cytokines involved in immune response, hematopoiesis, and homeostatic processes. Angiotensin-converting enzyme 2 (ACE2) is the canonical cell surface receptor for SARS-CoV-2. ACE2 together with angiotensin receptor types 1 and 2 and ACE2 are components of the renin-angiotensin system (RAS). Exacerbated production of cytokines, mainly IL-6, points to macrophages as key to understand differential COVID-19 severity. SARS-CoV-2 may modulate macrophage-mediated inflammation events by altering the balance between angiotensin II, which activates angiotensin receptor types 1 and 2, and angiotensin 1-7 and alamandine, which activate MAS proto-oncogene and MAS-related D receptors, respectively. In addition to macrophages, lung cells express RAS components; also, some lung cells are able to produce IL-6. Addressing how SARS-CoV-2 unbalances RAS functionality via ACE2 will help design therapies to attenuate a COVID-19-related cytokine storm.


Subject(s)
Betacoronavirus/metabolism , Coronavirus Infections/immunology , Interleukin-6/biosynthesis , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/immunology , Renin-Angiotensin System , Angiotensin I/metabolism , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus/immunology , COVID-19 , Coronavirus Infections/virology , Humans , Inflammation/immunology , Macrophages/immunology , Pandemics , Peptide Fragments/metabolism , Pneumonia, Viral/virology , Proto-Oncogene Proteins/metabolism , Receptor, Angiotensin, Type 1/metabolism , Receptor, Angiotensin, Type 2/metabolism , Receptors, G-Protein-Coupled/metabolism , Receptors, Virus/metabolism , SARS-CoV-2
11.
Clin Immunol ; 217: 108493, 2020 08.
Article in English | MEDLINE | ID: covidwho-574786

Subject(s)
Antigen-Antibody Complex/biosynthesis , Betacoronavirus/pathogenicity , Coronavirus Infections/immunology , Cytokine Release Syndrome/immunology , Immune Complex Diseases/immunology , Pneumonia, Viral/immunology , Severe Acute Respiratory Syndrome/immunology , Vasculitis/immunology , Antibodies, Viral/biosynthesis , Antigen-Antibody Complex/drug effects , Betacoronavirus/immunology , Blood Vessels/drug effects , Blood Vessels/immunology , Blood Vessels/pathology , Blood Vessels/virology , COVID-19 , Complement C3/antagonists & inhibitors , Complement C3/biosynthesis , Complement Inactivating Agents/therapeutic use , Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/virology , Humans , Immune Complex Diseases/complications , Immune Complex Diseases/drug therapy , Immune Complex Diseases/virology , Immunity, Humoral/drug effects , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Interleukin-6/antagonists & inhibitors , Interleukin-6/biosynthesis , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Receptors, Interleukin-1/antagonists & inhibitors , Receptors, Interleukin-1/biosynthesis , SARS-CoV-2 , Severe Acute Respiratory Syndrome/complications , Severe Acute Respiratory Syndrome/drug therapy , Severe Acute Respiratory Syndrome/virology , Severity of Illness Index , Vasculitis/complications , Vasculitis/drug therapy , Vasculitis/virology
12.
Clin Immunol ; 217: 108487, 2020 08.
Article in English | MEDLINE | ID: covidwho-436345

ABSTRACT

Coronavirus Disease 2019 (COVID-19) is an ongoing public health emergency and new knowledge about its immunopathogenic mechanisms is deemed necessary in the attempt to reduce the death burden, globally. For the first time in worldwide literature, we provide scientific evidence that in COVID-19 vasculitis a life-threatening escalation from type 2 T-helper immune response (humoral immunity) to type 3 hypersensitivity (immune complex disease) takes place. The subsequent deposition of immune complexes inside the vascular walls is supposed to induce a severe inflammatory state and a cytokine release syndrome, whose interleukin-6 is the key myokine, from the smooth muscle cells of blood vessels.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/immunology , Cytokine Release Syndrome/immunology , Immune Complex Diseases/immunology , Pneumonia, Viral/immunology , Severe Acute Respiratory Syndrome/immunology , Th2 Cells/immunology , Vasculitis/immunology , Aged , Antibodies, Viral/biosynthesis , Antigen-Antibody Complex/biosynthesis , Betacoronavirus/immunology , Blood Vessels/immunology , Blood Vessels/pathology , Blood Vessels/virology , COVID-19 , Complement C3/biosynthesis , Coronavirus Infections/complications , Coronavirus Infections/virology , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/virology , Disease Progression , Endothelial Cells/immunology , Endothelial Cells/pathology , Endothelial Cells/virology , Humans , Immune Complex Diseases/complications , Immune Complex Diseases/virology , Immunity, Humoral , Immunoglobulin G/biosynthesis , Immunoglobulin M/biosynthesis , Interleukin-6/biosynthesis , Male , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/virology , SARS-CoV-2 , Severe Acute Respiratory Syndrome/complications , Severe Acute Respiratory Syndrome/virology , Th2 Cells/pathology , Th2 Cells/virology , Vasculitis/complications , Vasculitis/virology
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