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1.
Pharmacol Res Perspect ; 10(2): e00940, 2022 04.
Article in English | MEDLINE | ID: covidwho-1712175

ABSTRACT

Anti-proinflammatory cytokine therapies against interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-1 are major advancements in treating inflammatory diseases, especially rheumatoid arthritis. Such therapies are mainly performed by injection of antibodies against cytokines or cytokine receptors. We initially found that the glycolytic inhibitor 2-deoxy-d-glucose (2-DG), a simple monosaccharide, attenuated cellular responses to IL-6 by inhibiting N-linked glycosylation of the IL-6 receptor gp130. Aglycoforms of gp130 did not bind to IL-6 or activate downstream intracellular signals that included Janus kinases. 2-DG completely inhibited dextran sodium sulfate-induced colitis, a mouse model for inflammatory bowel disease, and alleviated laminarin-induced arthritis in the SKG mouse, an experimental model for human rheumatoid arthritis. These diseases have been shown to be partially dependent on IL-6. We also found that 2-DG inhibited signals for other proinflammatory cytokines such as TNF-α, IL-1ß, and interferon -γ, and accordingly, prevented death by another inflammatory disease, lipopolysaccharide (LPS) shock. Furthermore, 2-DG prevented LPS shock, a model for a cytokine storm, and LPS-induced pulmonary inflammation, a model for acute respiratory distress syndrome of coronavirus disease 2019 (COVID-19). These results suggest that targeted therapies that inhibit cytokine receptor glycosylation are effective for treatment of various inflammatory diseases.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Deoxyglucose/pharmacology , Glycosylation/drug effects , Inflammation/prevention & control , Receptors, Cytokine/drug effects , Animals , Cells, Cultured , Cytokine Receptor gp130/antagonists & inhibitors , Cytokine Receptor gp130/metabolism , Cytokine Release Syndrome/prevention & control , Cytokines/metabolism , Inflammation/chemically induced , Janus Kinases/drug effects , Lipopolysaccharides , Mice , Mice, Inbred C57BL , Mice, Knockout , Receptors, Cytokine/immunology , Receptors, Cytokine/metabolism , Receptors, Interleukin-6/antagonists & inhibitors , Receptors, Interleukin-6/genetics , Receptors, Interleukin-6/metabolism
2.
J Interferon Cytokine Res ; 41(10): 355-359, 2021 10.
Article in English | MEDLINE | ID: covidwho-1554113
3.
J Biol Chem ; 296: 100745, 2021.
Article in English | MEDLINE | ID: covidwho-1213326

ABSTRACT

Fifty years ago, the first landmark structures of antibodies heralded the dawn of structural immunology. Momentum then started to build toward understanding how antibodies could recognize the vast universe of potential antigens and how antibody-combining sites could be tailored to engage antigens with high specificity and affinity through recombination of germline genes (V, D, J) and somatic mutation. Equivalent groundbreaking structures in the cellular immune system appeared some 15 to 20 years later and illustrated how processed protein antigens in the form of peptides are presented by MHC molecules to T cell receptors. Structures of antigen receptors in the innate immune system then explained their inherent specificity for particular microbial antigens including lipids, carbohydrates, nucleic acids, small molecules, and specific proteins. These two sides of the immune system act immediately (innate) to particular microbial antigens or evolve (adaptive) to attain high specificity and affinity to a much wider range of antigens. We also include examples of other key receptors in the immune system (cytokine receptors) that regulate immunity and inflammation. Furthermore, these antigen receptors use a limited set of protein folds to accomplish their various immunological roles. The other main players are the antigens themselves. We focus on surface glycoproteins in enveloped viruses including SARS-CoV-2 that enable entry and egress into host cells and are targets for the antibody response. This review covers what we have learned over the past half century about the structural basis of the immune response to microbial pathogens and how that information can be utilized to design vaccines and therapeutics.


Subject(s)
Adaptive Immunity , Antibodies, Viral/chemistry , Antigens, Viral/chemistry , Immunity, Innate , Receptors, Antigen, T-Cell/chemistry , Receptors, Cytokine/chemistry , SARS-CoV-2/immunology , Allergy and Immunology/history , Animals , Antibodies, Viral/genetics , Antibodies, Viral/immunology , Antibody Specificity , Antigen Presentation , Antigens, Viral/genetics , Antigens, Viral/immunology , COVID-19/immunology , COVID-19/virology , Crystallography/history , Crystallography/methods , History, 20th Century , History, 21st Century , Humans , Protein Folding , Protein Interaction Domains and Motifs , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/immunology , Receptors, Cytokine/genetics , Receptors, Cytokine/immunology , SARS-CoV-2/pathogenicity , V(D)J Recombination
4.
Mol Cell Proteomics ; 19(11): 1749-1759, 2020 11.
Article in English | MEDLINE | ID: covidwho-713514

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a highly contagious infection and threating the human lives in the world. The elevation of cytokines in blood is crucial to induce cytokine storm and immunosuppression in the transition of severity in COVID-19 patients. However, the comprehensive changes of serum proteins in COVID-19 patients throughout the SARS-CoV-2 infection is unknown. In this work, we developed a high-density antibody microarray and performed an in-depth proteomics analysis of serum samples collected from early COVID-19 (n = 15) and influenza (n = 13) patients. We identified a large set of differentially expressed proteins (n = 132) that participate in a landscape of inflammation and immune signaling related to the SARS-CoV-2 infection. Furthermore, the significant correlations of neutrophil and lymphocyte with the CCL2 and CXCL10 mediated cytokine signaling pathways was identified. These information are valuable for the understanding of COVID-19 pathogenesis, identification of biomarkers and development of the optimal anti-inflammation therapy.


Subject(s)
Blood Proteins/immunology , Coronavirus Infections/immunology , Cough/immunology , Cytokine Release Syndrome/immunology , Fever/immunology , Headache/immunology , Influenza, Human/immunology , Myalgia/immunology , Pneumonia, Viral/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Betacoronavirus/pathogenicity , Blood Proteins/genetics , COVID-19 , Child , Coronavirus Infections/genetics , Coronavirus Infections/physiopathology , Coronavirus Infections/virology , Cough/genetics , Cough/physiopathology , Cough/virology , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/physiopathology , Cytokine Release Syndrome/virology , Cytokines/genetics , Cytokines/immunology , Female , Fever/genetics , Fever/physiopathology , Fever/virology , Gene Expression Profiling , Gene Expression Regulation , Headache/genetics , Headache/physiopathology , Headache/virology , Humans , Influenza, Human/genetics , Influenza, Human/physiopathology , Influenza, Human/virology , Male , Middle Aged , Myalgia/genetics , Myalgia/physiopathology , Myalgia/virology , Orthomyxoviridae/pathogenicity , Pandemics , Pneumonia, Viral/genetics , Pneumonia, Viral/physiopathology , Pneumonia, Viral/virology , Protein Array Analysis , Proteome/genetics , Proteome/immunology , Receptors, Cytokine/genetics , Receptors, Cytokine/immunology , SARS-CoV-2 , Signal Transduction/immunology
5.
Brain Behav Immun ; 89: 559-568, 2020 10.
Article in English | MEDLINE | ID: covidwho-457154

ABSTRACT

The SARS-CoV-2 virus infects cells of the airway and lungs in humans causing the disease COVID-19. This disease is characterized by cough, shortness of breath, and in severe cases causes pneumonia and acute respiratory distress syndrome (ARDS) which can be fatal. Bronchial alveolar lavage fluid (BALF) and plasma from mild and severe cases of COVID-19 have been profiled using protein measurements and bulk and single cell RNA sequencing. Onset of pneumonia and ARDS can be rapid in COVID-19, suggesting a potential neuronal involvement in pathology and mortality. We hypothesized that SARS-CoV-2 infection drives changes in immune cell-derived factors that then interact with receptors expressed by the sensory neuronal innervation of the lung to further promote important aspects of disease severity, including ARDS. We sought to quantify how immune cells might interact with sensory innervation of the lung in COVID-19 using published data from patients, existing RNA sequencing datasets from human dorsal root ganglion neurons and other sources, and a genome-wide ligand-receptor pair database curated for pharmacological interactions relevant for neuro-immune interactions. Our findings reveal a landscape of ligand-receptor interactions in the lung caused by SARS-CoV-2 viral infection and point to potential interventions to reduce the burden of neurogenic inflammation in COVID-19 pulmonary disease. In particular, our work highlights opportunities for clinical trials with existing or under development rheumatoid arthritis and other (e.g. CCL2, CCR5 or EGFR inhibitors) drugs to treat high risk or severe COVID-19 cases.


Subject(s)
Bronchoalveolar Lavage Fluid/immunology , Coronavirus Infections/immunology , Cytokines/immunology , Lung/immunology , Lung/innervation , Pneumonia, Viral/immunology , Receptors, Cytokine/immunology , Sensory Receptor Cells/immunology , Antirheumatic Agents/therapeutic use , Betacoronavirus , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/metabolism , Cytokines/metabolism , Databases, Factual , Ganglia, Spinal , Humans , Lung/metabolism , Lung/physiopathology , Molecular Targeted Therapy , Nociceptors/metabolism , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/metabolism , RNA-Seq , Receptors, Cytokine/metabolism , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/metabolism , Respiratory Distress Syndrome/physiopathology , SARS-CoV-2 , Sensory Receptor Cells/metabolism , Transcriptome , Up-Regulation
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