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1.
Eur J Med Res ; 26(1): 146, 2021 Dec 17.
Article in English | MEDLINE | ID: covidwho-1582003

ABSTRACT

BACKGROUND: At the end of 2019, the world witnessed the emergence and ravages of a viral infection induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Also known as the coronavirus disease 2019 (COVID-19), it has been identified as a public health emergency of international concern (PHEIC) by the World Health Organization (WHO) because of its severity. METHODS: The gene data of 51 samples were extracted from the GSE150316 and GSE147507 data set and then processed by means of the programming language R, through which the differentially expressed genes (DEGs) that meet the standards were screened. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed on the selected DEGs to understand the functions and approaches of DEGs. The online tool STRING was employed to construct a protein-protein interaction (PPI) network of DEGs and, in turn, to identify hub genes. RESULTS: A total of 52 intersection genes were obtained through DEG identification. Through the GO analysis, we realized that the biological processes (BPs) that have the deepest impact on the human body after SARS-CoV-2 infection are various immune responses. By using STRING to construct a PPI network, 10 hub genes were identified, including IFIH1, DDX58, ISG15, EGR1, OASL, SAMD9, SAMD9L, XAF1, IFITM1, and TNFSF10. CONCLUSION: The results of this study will hopefully provide guidance for future studies on the pathophysiological mechanism of SARS-CoV-2 infection.


Subject(s)
COVID-19/genetics , Computational Biology/methods , Gene Expression Regulation/genetics , Lung/pathology , Protein Interaction Maps/genetics , COVID-19/pathology , Databases, Genetic , Gene Expression Profiling , Gene Ontology , Humans , Immunity, Humoral/genetics , Immunity, Humoral/immunology , Lung/virology , Neutrophil Activation/genetics , Neutrophil Activation/immunology , Neutrophils/immunology , SARS-CoV-2 , Transcriptome/genetics
2.
Int J Mol Sci ; 22(2)2021 Jan 08.
Article in English | MEDLINE | ID: covidwho-1389386

ABSTRACT

Neutrophils are primary effector cells of innate immunity and fight infection by phagocytosis and degranulation. Activated neutrophils also release neutrophil extracellular traps (NETs) in response to a variety of stimuli. These NETs are net-like complexes composed of cell-free DNA, histones and neutrophil granule proteins. Besides the evolutionarily conserved mechanism to capture and eliminate pathogens, NETs are also associated with pathophysiological processes of various diseases. Here, we elucidate the mechanisms of NET formation and their different implications in disease. We focused on autoinflammatory and cardiovascular disorders as the leading cause of death. Neutrophil extracellular traps are not only present in various cardiovascular diseases but play an essential role in atherosclerotic plaque formation, arterial and venous thrombosis, as well as in the development and progression of abdominal aortic aneurysms. Furthermore, NETosis can be considered as a source of autoantigens and maintains an inflammatory milieu promoting autoimmune diseases. Indeed, there is further need for research into the balance between NET induction, inhibition, and degradation in order to pharmacologically target NETs and their compounds without impairing the patient's immune defense. This review may be of interest to both basic scientists and clinicians to stimulate translational research and innovative clinical approaches.


Subject(s)
Autoimmune Diseases/immunology , Extracellular Traps/immunology , Neutrophils/immunology , Aortic Aneurysm, Abdominal/pathology , Autoimmune Diseases/pathology , Autoimmunity/immunology , COVID-19/immunology , COVID-19/pathology , Humans , Neutrophil Activation/immunology , Plaque, Atherosclerotic/pathology , Thrombosis/pathology
3.
J Infect Dis ; 224(4): 575-585, 2021 08 16.
Article in English | MEDLINE | ID: covidwho-1358459

ABSTRACT

Severe coronavirus disease 2019 (COVID-19) is associated with an overactive inflammatory response mediated by macrophages. Here, we analyzed the phenotype and function of neutrophils in patients with COVID-19. We found that neutrophils from patients with severe COVID-19 express high levels of CD11b and CD66b, spontaneously produce CXCL8 and CCL2, and show a strong association with platelets. Production of CXCL8 correlated with plasma concentrations of lactate dehydrogenase and D-dimer. Whole blood assays revealed that neutrophils from patients with severe COVID-19 show a clear association with immunoglobulin G (IgG) immune complexes. Moreover, we found that sera from patients with severe disease contain high levels of immune complexes and activate neutrophils through a mechanism partially dependent on FcγRII (CD32). Interestingly, when integrated in immune complexes, anti-severe acute respiratory syndrome coronavirus 2 IgG antibodies from patients with severe COVID-19 displayed a higher proinflammatory profile compared with antibodies from patients with mild disease. Our study suggests that IgG immune complexes might promote the acquisition of an inflammatory signature by neutrophils, worsening the course of COVID-19.


Subject(s)
Antibodies, Viral/immunology , Antigen-Antibody Complex/immunology , COVID-19/immunology , Immunoglobulin G/immunology , Neutrophil Activation/immunology , Adult , Aged , Antibodies, Viral/blood , Antigen-Antibody Complex/blood , Antigens, CD/immunology , CD11b Antigen/immunology , Cell Adhesion Molecules/immunology , Female , GPI-Linked Proteins/immunology , Humans , Immunoglobulin G/blood , Interleukin-8/immunology , Male , Middle Aged , Neutrophils/immunology , Receptors, IgG/immunology , SARS-CoV-2/immunology , Young Adult
4.
JCI Insight ; 6(14)2021 07 22.
Article in English | MEDLINE | ID: covidwho-1320461

ABSTRACT

BACKGROUNDIndividuals recovering from COVID-19 frequently experience persistent respiratory ailments, which are key elements of postacute sequelae of SARS-CoV-2 infection (PASC); however, little is known about the underlying biological factors that may direct lung recovery and the extent to which these are affected by COVID-19 severity.METHODSWe performed a prospective cohort study of individuals with persistent symptoms after acute COVID-19, collecting clinical data, pulmonary function tests, and plasma samples used for multiplex profiling of inflammatory, metabolic, angiogenic, and fibrotic factors.RESULTSSixty-one participants were enrolled across 2 academic medical centers at a median of 9 weeks (interquartile range, 6-10 weeks) after COVID-19 illness: n = 13 participants (21%) had mild COVID-19 and were not hospitalized, n = 30 participants (49%) were hospitalized but were considered noncritical, and n = 18 participants (30%) were hospitalized and in the intensive care unit (ICU). Fifty-three participants (85%) had lingering symptoms, most commonly dyspnea (69%) and cough (58%). Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and diffusing capacity for carbon monoxide (DLCO) declined as COVID-19 severity increased (P < 0.05) but these values did not correlate with respiratory symptoms. Partial least-squares discriminant analysis of plasma biomarker profiles clustered participants by past COVID-19 severity. Lipocalin-2 (LCN2), MMP-7, and HGF identified by our analysis were significantly higher in the ICU group (P < 0.05), inversely correlated with FVC and DLCO (P < 0.05), and were confirmed in a separate validation cohort (n = 53).CONCLUSIONSubjective respiratory symptoms are common after acute COVID-19 illness but do not correlate with COVID-19 severity or pulmonary function. Host response profiles reflecting neutrophil activation (LCN2), fibrosis signaling (MMP-7), and alveolar repair (HGF) track with lung impairment and may be novel therapeutic or prognostic targets.FundingNational Heart, Lung, and Blood Institute (K08HL130557 and R01HL142818), American Heart Association (Transformational Project Award), the DeLuca Foundation Award, a donation from Jack Levin to the Benign Hematology Program at Yale University, and Duke University.


Subject(s)
COVID-19/complications , Hepatocyte Growth Factor/analysis , Lipocalin-2/analysis , Matrix Metalloproteinase 7/analysis , Pulmonary Fibrosis , Respiratory Function Tests , COVID-19/diagnosis , COVID-19/immunology , COVID-19/physiopathology , Cough/diagnosis , Cough/etiology , Dyspnea/diagnosis , Dyspnea/etiology , Female , Humans , Lung/metabolism , Lung/pathology , Lung/physiopathology , Male , Middle Aged , Neutrophil Activation/immunology , Prognosis , Pulmonary Fibrosis/diagnosis , Pulmonary Fibrosis/etiology , Pulmonary Fibrosis/metabolism , Recovery of Function/immunology , Respiratory Function Tests/methods , Respiratory Function Tests/statistics & numerical data , SARS-CoV-2 , Severity of Illness Index
5.
J Infect Dis ; 224(4): 575-585, 2021 08 16.
Article in English | MEDLINE | ID: covidwho-1169670

ABSTRACT

Severe coronavirus disease 2019 (COVID-19) is associated with an overactive inflammatory response mediated by macrophages. Here, we analyzed the phenotype and function of neutrophils in patients with COVID-19. We found that neutrophils from patients with severe COVID-19 express high levels of CD11b and CD66b, spontaneously produce CXCL8 and CCL2, and show a strong association with platelets. Production of CXCL8 correlated with plasma concentrations of lactate dehydrogenase and D-dimer. Whole blood assays revealed that neutrophils from patients with severe COVID-19 show a clear association with immunoglobulin G (IgG) immune complexes. Moreover, we found that sera from patients with severe disease contain high levels of immune complexes and activate neutrophils through a mechanism partially dependent on FcγRII (CD32). Interestingly, when integrated in immune complexes, anti-severe acute respiratory syndrome coronavirus 2 IgG antibodies from patients with severe COVID-19 displayed a higher proinflammatory profile compared with antibodies from patients with mild disease. Our study suggests that IgG immune complexes might promote the acquisition of an inflammatory signature by neutrophils, worsening the course of COVID-19.


Subject(s)
Antibodies, Viral/immunology , Antigen-Antibody Complex/immunology , COVID-19/immunology , Immunoglobulin G/immunology , Neutrophil Activation/immunology , Adult , Aged , Antibodies, Viral/blood , Antigen-Antibody Complex/blood , Antigens, CD/immunology , CD11b Antigen/immunology , Cell Adhesion Molecules/immunology , Female , GPI-Linked Proteins/immunology , Humans , Immunoglobulin G/blood , Interleukin-8/immunology , Male , Middle Aged , Neutrophils/immunology , Receptors, IgG/immunology , SARS-CoV-2/immunology , Young Adult
6.
EBioMedicine ; 65: 103262, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1124859

ABSTRACT

BACKGROUND: The coronavirus disease-19 (COVID-19) pandemic has cost lives and economic hardships globally. Various studies have found a number of different factors, such as hyperinflammation and exhausted/suppressed T cell responses to the etiological SARS coronavirus-2 (SARS-CoV-2), being associated with severe COVID-19. However, sieving the causative from associative factors of respiratory dysfunction has remained rudimentary. METHODS: We postulated that the host responses causative of respiratory dysfunction would track most closely with disease progression and resolution and thus be differentiated from other factors that are statistically associated with but not causative of severe COVID-19. To track the temporal dynamics of the host responses involved, we examined the changes in gene expression in whole blood of 6 severe and 4 non-severe COVID-19 patients across 15 different timepoints spanning the nadir of respiratory function. FINDINGS: We found that neutrophil activation but not type I interferon signaling transcripts tracked most closely with disease progression and resolution. Moreover, transcripts encoding for protein phosphorylation, particularly the serine-threonine kinases, many of which have known T cell proliferation and activation functions, were increased after and may thus contribute to the upswing of respiratory function. Notably, these associative genes were targeted by dexamethasone, but not methylprednisolone, which is consistent with efficacy outcomes in clinical trials. INTERPRETATION: Our findings suggest neutrophil activation as a critical factor of respiratory dysfunction in COVID-19. Drugs that target this pathway could be potentially repurposed for the treatment of severe COVID-19. FUNDING: This study was sponsored in part by a generous gift from The Hour Glass. EEO and JGL are funded by the National Medical Research Council of Singapore, through the Clinician Scientist Awards awarded by the National Research Foundation of Singapore.


Subject(s)
COVID-19/pathology , Lymphocyte Activation/immunology , Neutrophil Activation/immunology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Adult , Aged , Disease Progression , Drug Repositioning , Female , Gene Expression/genetics , Gene Expression Profiling , Humans , Male , Middle Aged , Neutrophils/immunology , Prospective Studies , T-Lymphocytes/immunology
7.
Int Immunol ; 33(4): 241-247, 2021 03 31.
Article in English | MEDLINE | ID: covidwho-1066348

ABSTRACT

An expanded myeloid cell compartment is a hallmark of severe coronavirus disease 2019 (COVID-19). However, data regarding myeloid cell expansion have been collected in Europe, where the mortality rate by COVID-19 is greater than those in other regions including Japan. Thus, characteristics of COVID-19-induced myeloid cell subsets remain largely unknown in the regions with low mortality rates. Here, we analyzed cellular dynamics of myeloid-derived suppressor cell (MDSC) subsets and examined whether any of them correlate with disease severity and prognosis, using blood samples from Japanese COVID-19 patients. We observed that polymorphonuclear (PMN)-MDSCs, but not other MDSC subsets, transiently expanded in severe cases but not in mild or moderate cases. Contrary to previous studies in Europe, this subset selectively expanded in survivors of severe cases and subsided before discharge, but such transient expansion was not observed in non-survivors in Japanese cohort. Analysis of plasma cytokine/chemokine levels revealed positive correlation of PMN-MDSC frequencies with IL-8 levels, indicating the involvement of IL-8 on recruitment of PMN-MDSCs to peripheral blood following the onset of severe COVID-19. Our data indicate that transient expansion of the PMN-MDSC subset results in improved clinical outcome. Thus, this myeloid cell subset may be a predictor of prognosis in cases of severe COVID-19 in Japan.


Subject(s)
COVID-19/pathology , Interleukin-8/blood , Myeloid-Derived Suppressor Cells/immunology , Neutrophils/immunology , SARS-CoV-2/immunology , Humans , Interleukin-8/immunology , Japan , Leukocyte Count , Myeloid Cells/immunology , Neutrophil Activation/immunology
8.
Sci Rep ; 10(1): 22418, 2020 12 29.
Article in English | MEDLINE | ID: covidwho-997951

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over forty million patients worldwide. Although most coronavirus disease 2019 (COVID-19) patients have a good prognosis, some develop severe illness. Markers that define disease severity or predict clinical outcome need to be urgently developed as the mortality rate in critical cases is approximately 61.5%. In the present study, we performed in-depth proteome profiling of undepleted plasma from eight COVID-19 patients. Quantitative proteomic analysis using the BoxCar method revealed that 91 out of 1222 quantified proteins were differentially expressed depending on the severity of COVID-19. Importantly, we found 76 proteins, previously not reported, which could be novel prognostic biomarker candidates. Our plasma proteome signatures captured the host response to SARS-CoV-2 infection, thereby highlighting the role of neutrophil activation, complement activation, platelet function, and T cell suppression as well as proinflammatory factors upstream and downstream of interleukin-6, interleukin-1B, and tumor necrosis factor. Consequently, this study supports the development of blood biomarkers and potential therapeutic targets to aid clinical decision-making and subsequently improve prognosis of COVID-19.


Subject(s)
Blood Proteins/analysis , COVID-19/blood , Severity of Illness Index , Adult , Aged , Biomarkers/blood , COVID-19/mortality , COVID-19/pathology , Chromatography, High Pressure Liquid , Complement Activation/immunology , Cytokines/blood , Gene Expression Profiling , Humans , Mass Spectrometry , Middle Aged , Neutrophil Activation/immunology , Platelet Activation/immunology , Proteome/metabolism , SARS-CoV-2 , Suppressor Factors, Immunologic/blood , T-Lymphocytes/immunology
9.
Epigenomics ; 12(22): 1969-1981, 2020 11.
Article in English | MEDLINE | ID: covidwho-948022

ABSTRACT

Aim: To elucidate the transcriptional characteristics of COVID-19. Materials & methods: We utilized an integrative approach to comprehensively analyze the transcriptional features of both COVID-19 patients and SARS-CoV-2 infected cells. Results: Widespread infiltration of immune cells was observed. We identified 233 genes that were codifferentially expressed in both bronchoalveolar lavage fluid and lung samples of COVID-19 patients. Functional analysis suggested upregulated genes were related to immune response such as neutrophil activation and antivirus response, while downregulated genes were associated with cell adhesion. Finally, we identified LCN2, STAT1 and UBE2L6 as core genes during SARS-CoV-2 infection. Conclusion: The identification of core genes involved in COVID-19 can provide us with more insights into the molecular features of COVID-19.


Subject(s)
COVID-19/pathology , Lipocalin-2/genetics , SARS-CoV-2/immunology , STAT1 Transcription Factor/genetics , Ubiquitin-Conjugating Enzymes/genetics , A549 Cells , Bronchoalveolar Lavage Fluid/cytology , COVID-19/immunology , Cell Adhesion/genetics , Cell Adhesion/physiology , Cell Line, Tumor , Cytokines/blood , Humans , Lung/immunology , Neutrophil Activation/genetics , Neutrophil Activation/immunology , SARS-CoV-2/genetics , Transcription, Genetic/genetics
10.
PLoS One ; 15(10): e0240012, 2020.
Article in English | MEDLINE | ID: covidwho-881156

ABSTRACT

COVID-19 or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appeared throughout the World and currently affected more than 9 million people and caused the death of around 470,000 patients. The novel strain of the coronavirus disease is transmittable at a devastating rate with a high rate of severe hospitalization even more so for the elderly population. Naso-oro-pharyngeal swab samples as the first step towards detecting suspected infection of SARS-CoV-2 provides a non-invasive method for PCR testing at a high confidence rate. Furthermore, proteomics analysis of PCR positive and negative naso-oropharyngeal samples provides information on the molecular level which highlights disease pathology. Samples from 15 PCR positive cases and 15 PCR negative cases were analyzed with nanoLC-MS/MS to identify the differentially expressed proteins. Proteomic analyses identified 207 proteins across the sample set and 17 of them were statistically significant. Protein-protein interaction analyses emphasized pathways like Neutrophil degranulation, Innate Immune System, Antimicrobial Peptides. Neutrophil Elastase (ELANE), Azurocidin (AZU1), Myeloperoxidase (MPO), Myeloblastin (PRTN3), Cathepsin G (CTSG) and Transcobalamine-1 (TCN1) were found to be significantly altered in naso-oropharyngeal samples of SARS-CoV-2 patients. The identified proteins are linked to alteration in the innate immune system specifically via neutrophil degranulation and NETosis.


Subject(s)
Betacoronavirus/genetics , Cell Degranulation/immunology , Coronavirus Infections/immunology , Nasopharynx/virology , Neutrophil Activation/immunology , Neutrophils/immunology , Pneumonia, Viral/immunology , Proteome , Up-Regulation , Adult , COVID-19 , Chromatography, Liquid/methods , Coronavirus Infections/virology , Female , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/virology , Protein Interaction Maps , Proteomics/methods , Real-Time Polymerase Chain Reaction , SARS-CoV-2 , Tandem Mass Spectrometry/methods , Young Adult
11.
Pathog Dis ; 78(4)2020 06 01.
Article in English | MEDLINE | ID: covidwho-646518

ABSTRACT

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) around the world has led to a pandemic with high morbidity and mortality. However, there are no effective drugs to prevent and treat the disease. Transcriptome-based drug repositioning, identifying new indications for old drugs, is a powerful tool for drug development. Using bronchoalveolar lavage fluid transcriptome data of COVID-19 patients, we found that the endocytosis and lysosome pathways are highly involved in the disease and that the regulation of genes involved in neutrophil degranulation was disrupted, suggesting an intense battle between SARS-CoV-2 and humans. Furthermore, we implemented a coexpression drug repositioning analysis, cogena, and identified two antiviral drugs (saquinavir and ribavirin) and several other candidate drugs (such as dinoprost, dipivefrine, dexamethasone and (-)-isoprenaline). Notably, the two antiviral drugs have also previously been identified using molecular docking methods, and ribavirin is a recommended drug in the diagnosis and treatment protocol for COVID pneumonia (trial version 5-7) published by the National Health Commission of the P.R. of China. Our study demonstrates the value of the cogena-based drug repositioning method for emerging infectious diseases, improves our understanding of SARS-CoV-2-induced disease, and provides potential drugs for the prevention and treatment of COVID-19 pneumonia.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Drug Repositioning , Pneumonia, Viral/drug therapy , Ribavirin/pharmacology , Saquinavir/pharmacology , Bronchoalveolar Lavage Fluid/chemistry , COVID-19 , Cell Degranulation/immunology , Endocytosis/immunology , Gene Expression Profiling , Humans , Lysosomes/immunology , Molecular Docking Simulation , Neutrophil Activation/immunology , Pandemics , SARS-CoV-2 , Transcriptome
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