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2.
Front Immunol ; 13: 811430, 2022.
Article in English | MEDLINE | ID: covidwho-1731772

ABSTRACT

Despite significant research efforts, treatment options for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain limited. This is due in part to a lack of therapeutics that increase host defense to the virus. Replication of SARS-CoV-2 in lung tissue is associated with marked infiltration of macrophages and activation of innate immune inflammatory responses that amplify tissue injury. Antagonists of the androgen (AR) and glucocorticoid (GR) receptors have shown efficacy in models of COVID-19 and in clinical studies because the cell surface proteins required for viral entry, angiotensin converting enzyme 2 (ACE2) and the transmembrane protease, serine 2 (TMPRSS2), are transcriptionally regulated by these receptors. We postulated that the GR and AR modulator, PT150, would reduce infectivity of SARS-CoV-2 and prevent inflammatory lung injury in the Syrian golden hamster model of COVID-19 by down-regulating expression of critical genes regulated through these receptors. Animals were infected intranasally with 2.5 × 104 TCID50/ml equivalents of SARS-CoV-2 (strain 2019-nCoV/USA-WA1/2020) and PT150 was administered by oral gavage at 30 and 100 mg/Kg/day for a total of 7 days. Animals were examined at 3, 5 and 7 days post-infection (DPI) for lung histopathology, viral load and production of proteins regulating the progression of SARS-CoV-2 infection. Results indicated that oral administration of PT150 caused a dose-dependent decrease in replication of SARS-CoV-2 in lung, as well as in expression of ACE2 and TMPRSS2. Lung hypercellularity and infiltration of macrophages and CD4+ T-cells were dramatically decreased in PT150-treated animals, as was tissue damage and expression of IL-6. Molecular docking studies suggest that PT150 binds to the co-activator interface of the ligand-binding domain of both AR and GR, thereby acting as an allosteric modulator and transcriptional repressor of these receptors. Phylogenetic analysis of AR and GR revealed a high degree of sequence identity maintained across multiple species, including humans, suggesting that the mechanism of action and therapeutic efficacy observed in Syrian hamsters would likely be predictive of positive outcomes in patients. PT150 is therefore a strong candidate for further clinical development for the treatment of COVID-19 across variants of SARS-CoV-2.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Glucocorticoids/metabolism , Immunity, Innate/drug effects , Inflammation/drug therapy , Receptors, Androgen/metabolism , Virus Internalization/drug effects , Animals , COVID-19/metabolism , Disease Models, Animal , Female , Inflammation/metabolism , Inflammation/virology , Lung/virology , Male , Mesocricetus , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism , Serine Endopeptidases/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Viral Load/drug effects
3.
Sci Adv ; 8(8): eabi6110, 2022 Feb 25.
Article in English | MEDLINE | ID: covidwho-1714330

ABSTRACT

The spread of SARS-CoV-2 and ongoing COVID-19 pandemic underscores the need for new treatments. Here we report that cannabidiol (CBD) inhibits infection of SARS-CoV-2 in cells and mice. CBD and its metabolite 7-OH-CBD, but not THC or other congeneric cannabinoids tested, potently block SARS-CoV-2 replication in lung epithelial cells. CBD acts after viral entry, inhibiting viral gene expression and reversing many effects of SARS-CoV-2 on host gene transcription. CBD inhibits SARS-CoV-2 replication in part by up-regulating the host IRE1α RNase endoplasmic reticulum (ER) stress response and interferon signaling pathways. In matched groups of human patients from the National COVID Cohort Collaborative, CBD (100 mg/ml oral solution per medical records) had a significant negative association with positive SARS-CoV-2 tests. This study highlights CBD as a potential preventative agent for early-stage SARS-CoV-2 infection and merits future clinical trials. We caution against use of non-medical formulations including edibles, inhalants or topicals as a preventative or treatment therapy at the present time.


Subject(s)
Antiviral Agents/pharmacology , Cannabidiol/pharmacology , Host-Pathogen Interactions/drug effects , Immunity, Innate/drug effects , SARS-CoV-2/drug effects , A549 Cells , Animals , Antiviral Agents/chemistry , COVID-19/drug therapy , COVID-19/virology , Cannabidiol/chemistry , Cannabidiol/metabolism , Chlorocebus aethiops , Endoplasmic Reticulum Stress/drug effects , Endoribonucleases/genetics , Endoribonucleases/metabolism , Epithelial Cells/virology , Female , Gene Expression Regulation, Viral/drug effects , Host-Pathogen Interactions/physiology , Humans , Interferons/metabolism , Mice , /metabolism , SARS-CoV-2/physiology , Vero Cells , Virus Internalization/drug effects , Virus Replication/drug effects
4.
Signal Transduct Target Ther ; 7(1): 57, 2022 02 23.
Article in English | MEDLINE | ID: covidwho-1702971

ABSTRACT

The coronavirus disease 2019 (COVID-19) is a highly transmissible disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that poses a major threat to global public health. Although COVID-19 primarily affects the respiratory system, causing severe pneumonia and acute respiratory distress syndrome in severe cases, it can also result in multiple extrapulmonary complications. The pathogenesis of extrapulmonary damage in patients with COVID-19 is probably multifactorial, involving both the direct effects of SARS-CoV-2 and the indirect mechanisms associated with the host inflammatory response. Recognition of features and pathogenesis of extrapulmonary complications has clinical implications for identifying disease progression and designing therapeutic strategies. This review provides an overview of the extrapulmonary complications of COVID-19 from immunological and pathophysiologic perspectives and focuses on the pathogenesis and potential therapeutic targets for the management of COVID-19.


Subject(s)
Acute Kidney Injury/complications , COVID-19/complications , Cytokine Release Syndrome/complications , Disseminated Intravascular Coagulation/complications , Lymphopenia/complications , Myocarditis/complications , Pulmonary Embolism/complications , Acute Kidney Injury/drug therapy , Acute Kidney Injury/immunology , Acute Kidney Injury/virology , Anticoagulants/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/immunology , COVID-19/virology , Clinical Trials as Topic , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/virology , Disseminated Intravascular Coagulation/drug therapy , Disseminated Intravascular Coagulation/immunology , Disseminated Intravascular Coagulation/virology , Endothelial Cells/drug effects , Endothelial Cells/immunology , Endothelial Cells/virology , Humans , Immunity, Innate/drug effects , Immunologic Factors/therapeutic use , Lymphopenia/drug therapy , Lymphopenia/immunology , Lymphopenia/virology , Myocarditis/drug therapy , Myocarditis/immunology , Myocarditis/virology , Pulmonary Embolism/drug therapy , Pulmonary Embolism/immunology , Pulmonary Embolism/virology , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/immunology , SARS-CoV-2/drug effects , SARS-CoV-2/growth & development , SARS-CoV-2/pathogenicity
5.
J Virol ; 95(24): e0117421, 2021 11 23.
Article in English | MEDLINE | ID: covidwho-1691429

ABSTRACT

Defective interfering particles (DIPs) of influenza A virus (IAV) are naturally occurring mutants that have an internal deletion in one of their eight viral RNA (vRNA) segments, rendering them propagation-incompetent. Upon coinfection with infectious standard virus (STV), DIPs interfere with STV replication through competitive inhibition. Thus, DIPs are proposed as potent antivirals for treatment of the influenza disease. To select corresponding candidates, we studied de novo generation of DIPs and propagation competition between different defective interfering (DI) vRNAs in an STV coinfection scenario in cell culture. A small-scale two-stage cultivation system that allows long-term semi-continuous propagation of IAV and its DIPs was used. Strong periodic oscillations in virus titers were observed due to the dynamic interaction of DIPs and STVs. Using next-generation sequencing, we detected a predominant formation and accumulation of DI vRNAs on the polymerase-encoding segments. Short DI vRNAs accumulated to higher fractions than longer ones, indicating a replication advantage, yet an optimum fragment length was observed. Some DI vRNAs showed breaking points in a specific part of their bundling signal (belonging to the packaging signal), suggesting its dispensability for DI vRNA propagation. Over a total cultivation time of 21 days, several individual DI vRNAs accumulated to high fractions, while others decreased. Using reverse genetics for IAV, purely clonal DIPs derived from highly replicating DI vRNAs were generated. We confirm that these DIPs exhibit a superior in vitro interfering efficacy compared to DIPs derived from lowly accumulated DI vRNAs and suggest promising candidates for efficacious antiviral treatment. IMPORTANCE Defective interfering particles (DIPs) emerge naturally during viral infection and typically show an internal deletion in the viral genome. Thus, DIPs are propagation-incompetent. Previous research suggests DIPs as potent antiviral compounds for many different virus families due to their ability to interfere with virus replication by competitive inhibition. For instance, the administration of influenza A virus (IAV) DIPs resulted in a rescue of mice from an otherwise lethal IAV dose. Moreover, no apparent toxic effects were observed when only DIPs were administered to mice and ferrets. IAV DIPs show antiviral activity against many different IAV strains, including pandemic and highly pathogenic avian strains, and even against nonhomologous viruses, such as SARS-CoV-2, by stimulation of innate immunity. Here, we used a cultivation/infection system, which exerted selection pressure toward accumulation of highly competitive IAV DIPs. These DIPs showed a superior interfering efficacy in vitro, and we suggest them for effective antiviral therapy.


Subject(s)
Antiviral Agents/pharmacology , Drug Design/methods , Influenza A virus , Influenza, Human/virology , RNA, Viral , Animals , Cell Culture Techniques , Cell Line , Defective Viruses/genetics , Dogs , Gene Deletion , Genome, Viral , Humans , Immunity, Innate/drug effects , Madin Darby Canine Kidney Cells , Oscillometry , Real-Time Polymerase Chain Reaction , Viral Load/drug effects , Virus Replication/drug effects
6.
J Med Chem ; 65(3): 2558-2570, 2022 02 10.
Article in English | MEDLINE | ID: covidwho-1655430

ABSTRACT

Safe and effective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants are the best approach to successfully combat the COVID-19 pandemic. The receptor-binding domain (RBD) of the viral spike protein is a major target to develop candidate vaccines. α-Galactosylceramide (αGalCer), a potent invariant natural killer T cell (iNKT) agonist, was site-specifically conjugated to the N-terminus of the RBD to form an adjuvant-protein conjugate, which was anchored on the liposome surface. This is the first time that an iNKT cell agonist was conjugated to the protein antigen. Compared to the unconjugated RBD/αGalCer mixture, the αGalCer-RBD conjugate induced significantly stronger humoral and cellular responses. The conjugate vaccine also showed effective cross-neutralization to all variants of concern (B.1.1.7/alpha, B.1.351/beta, P.1/gamma, B.1.617.2/delta, and B.1.1.529/omicron). These results suggest that the self-adjuvanting αGalCer-RBD has great potential to be an effective COVID-19 vaccine candidate, and this strategy might be useful for designing various subunit vaccines.


Subject(s)
COVID-19 Vaccines/therapeutic use , COVID-19/therapy , Galactosylceramides/therapeutic use , Peptide Fragments/therapeutic use , SARS-CoV-2/immunology , Vaccines, Conjugate/therapeutic use , Adjuvants, Immunologic/chemistry , Adjuvants, Immunologic/therapeutic use , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19 Vaccines/chemistry , COVID-19 Vaccines/immunology , Female , Galactosylceramides/chemistry , Galactosylceramides/immunology , Immunity, Humoral/drug effects , Immunity, Innate/drug effects , Interferon-gamma/metabolism , Liposomes/chemistry , Liposomes/immunology , Liposomes/therapeutic use , Mice, Inbred BALB C , Peptide Fragments/chemistry , Peptide Fragments/immunology , Protein Domains , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/therapeutic use , Vaccines, Conjugate/chemistry , Vaccines, Conjugate/immunology
7.
Life Sci ; 294: 120368, 2022 Apr 01.
Article in English | MEDLINE | ID: covidwho-1654900

ABSTRACT

The fear of SARS-CoV-2 infection is due to its high mortality related to seasonal flu. To date, few medicines have been developed to significantly reduce the mortality of the severe COVID-19 patients, especially those requiring tracheal intubation. The severity and mortality of SARS-CoV-2 infection not only depend on the viral virulence, but are primarily determined by the cytokine storm and the destructive inflammation driven by the host immune reaction. Thus, to target the host immune response might be a better strategy to combat this pandemic. Melatonin is a molecule with multiple activities on a virus infection. These include that it downregulates the overreaction of innate immune response to suppress inflammation, promotes the adaptive immune reaction to enhance antibody formation, inhibits the entrance of the virus into the cell as well as limits its replication. These render it a potentially excellent candidate for treatment of the severe COVID-19 cases. Several clinical trials have confirmed that melatonin when added to the conventional therapy significantly reduces the mortality of the severe COVID-19 patients. The cost of melatonin is a small fraction of those medications approved by FDA for emergency use to treat COVID-19. Because of its self-administered, low cost and high safety margin, melatonin could be made available to every country in the world at an affordable cost. We recommend melatonin be used to treat severe COVID-19 patients with the intent of reducing mortality. If successful, it would make the SARS-CoV-2 pandemic less fearful and help to return life back to normalcy.


Subject(s)
COVID-19/drug therapy , Melatonin/therapeutic use , SARS-CoV-2 , Anti-Inflammatory Agents , Antioxidants , COVID-19/immunology , COVID-19/mortality , Cytokine Release Syndrome/drug therapy , Humans , Immunity, Innate/drug effects , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Virus Replication/drug effects
8.
Nat Commun ; 13(1): 440, 2022 01 21.
Article in English | MEDLINE | ID: covidwho-1641960

ABSTRACT

Dysregulated immune responses against the SARS-CoV-2 virus are instrumental in severe COVID-19. However, the immune signatures associated with immunopathology are poorly understood. Here we use multi-omics single-cell analysis to probe the dynamic immune responses in hospitalized patients with stable or progressive course of COVID-19, explore V(D)J repertoires, and assess the cellular effects of tocilizumab. Coordinated profiling of gene expression and cell lineage protein markers shows that S100Ahi/HLA-DRlo classical monocytes and activated LAG-3hi T cells are hallmarks of progressive disease and highlights the abnormal MHC-II/LAG-3 interaction on myeloid and T cells, respectively. We also find skewed T cell receptor repertories in expanded effector CD8+ clones, unmutated IGHG+ B cell clones, and mutated B cell clones with stable somatic hypermutation frequency over time. In conclusion, our in-depth immune profiling reveals dyssynchrony of the innate and adaptive immune interaction in progressive COVID-19.


Subject(s)
Adaptive Immunity/immunology , COVID-19/immunology , Gene Expression Profiling/methods , Immunity, Innate/immunology , SARS-CoV-2/immunology , Single-Cell Analysis/methods , Adaptive Immunity/drug effects , Adaptive Immunity/genetics , Aged , Antibodies, Monoclonal, Humanized/therapeutic use , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , COVID-19/drug therapy , COVID-19/genetics , Cells, Cultured , Female , Gene Expression Regulation/drug effects , Gene Expression Regulation/immunology , Humans , Immunity, Innate/drug effects , Immunity, Innate/genetics , Male , RNA-Seq/methods , Receptors, Antigen, B-Cell/genetics , Receptors, Antigen, B-Cell/immunology , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/immunology , SARS-CoV-2/drug effects , SARS-CoV-2/physiology
9.
Int Immunopharmacol ; 104: 108516, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1611782

ABSTRACT

Coronavirus disease 2019 (Covid-19) is a worldwide infectious disease caused by severe acute respiratory coronavirus 2 (SARS-CoV-2). In severe SARS-CoV-2 infection, there is severe inflammatory reactions due to neutrophil recruitments and infiltration in the different organs with the formation of neutrophil extracellular traps (NETs), which involved various complications of SARS-CoV-2 infection. Therefore, the objective of the present review was to explore the potential role of NETs in the pathogenesis of SARS-CoV-2 infection and to identify the targeting drugs against NETs in Covid-19 patients. Different enzyme types are involved in the formation of NETs, such as neutrophil elastase (NE), which degrades nuclear protein and release histones, peptidyl arginine deiminase type 4 (PADA4), which releases chromosomal DNA and gasdermin D, which creates pores in the NTs cell membrane that facilitating expulsion of NT contents. Despite of the beneficial effects of NETs in controlling of invading pathogens, sustained formations of NETs during respiratory viral infections are associated with collateral tissue injury. Excessive development of NETs in SARS-CoV-2 infection is linked with the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) due to creation of the NETs-IL-1ß loop. Also, aberrant NTs activation alone or through NETs formation may augment SARS-CoV-2-induced cytokine storm (CS) and macrophage activation syndrome (MAS) in patients with severe Covid-19. Furthermore, NETs formation in SARS-CoV-2 infection is associated with immuno-thrombosis and the development of ALI/ARDS. Therefore, anti-NETs therapy of natural or synthetic sources may mitigate SARS-CoV-2 infection-induced exaggerated immune response, hyperinflammation, immuno-thrombosis, and other complications.


Subject(s)
Acute Lung Injury/immunology , Anti-Inflammatory Agents/pharmacology , COVID-19/immunology , Cytokine Release Syndrome/immunology , Extracellular Traps/immunology , Acute Lung Injury/prevention & control , Acute Lung Injury/virology , Anti-Inflammatory Agents/therapeutic use , COVID-19/complications , COVID-19/drug therapy , COVID-19/virology , Cytokine Release Syndrome/prevention & control , Cytokine Release Syndrome/virology , Extracellular Traps/drug effects , Extracellular Traps/metabolism , Humans , Immunity, Innate/drug effects , Leukocyte Elastase/antagonists & inhibitors , Leukocyte Elastase/metabolism , Neutrophil Infiltration/drug effects , Phosphate-Binding Proteins/antagonists & inhibitors , Phosphate-Binding Proteins/metabolism , Pore Forming Cytotoxic Proteins/antagonists & inhibitors , Pore Forming Cytotoxic Proteins/metabolism , Protein-Arginine Deiminase Type 4/antagonists & inhibitors , Protein-Arginine Deiminase Type 4/metabolism , SARS-CoV-2/immunology
10.
Nutrients ; 13(2)2021 Jan 23.
Article in English | MEDLINE | ID: covidwho-1575478

ABSTRACT

SARS-CoV-2 is a newly emerging virus that currently lacks curative treatments. Lactoferrin (LF) is a naturally occurring non-toxic glycoprotein with broad-spectrum antiviral, immunomodulatory and anti-inflammatory effects. In this study, we assessed the potential of LF in the prevention of SARS-CoV-2 infection in vitro. Antiviral immune response gene expression was analyzed by qRT-PCR in uninfected Caco-2 intestinal epithelial cells treated with LF. An infection assay for SARS-CoV-2 was performed in Caco-2 cells treated or not with LF. SARS-CoV-2 titer was determined by qRT-PCR, plaque assay and immunostaining. Inflammatory and anti-inflammatory cytokine production was determined by qRT-PCR. LF significantly induced the expression of IFNA1, IFNB1, TLR3, TLR7, IRF3, IRF7 and MAVS genes. Furthermore, LF partially inhibited SARS-CoV-2 infection and replication in Caco-2 intestinal epithelial cells. Our in vitro data support LF as an immune modulator of the antiviral immune response with moderate effects against SARS-CoV-2 infection.


Subject(s)
Antiviral Agents/pharmacology , COVID-19 , Gene Expression Regulation , Immunity, Innate/drug effects , Lactoferrin/pharmacology , SARS-CoV-2/immunology , Animals , COVID-19/immunology , COVID-19/pathology , COVID-19/prevention & control , Caco-2 Cells , Chlorocebus aethiops , Gene Expression Regulation/drug effects , Gene Expression Regulation/immunology , Humans , Vero Cells
11.
Int J Mol Sci ; 22(22)2021 Nov 19.
Article in English | MEDLINE | ID: covidwho-1524027

ABSTRACT

Severe outcomes of COVID-19 are associated with pathological response of the immune system to the SARS-CoV-2 infection. Emerging evidence suggests that an interaction may exist between COVID-19 pathogenesis and a broad range of xenobiotics, resulting in significant increases in death rates in highly exposed populations. Therefore, a better understanding of the molecular basis of the interaction between SARS-CoV-2 infection and chemical exposures may open opportunities for better preventive and therapeutic interventions. We attempted to gain mechanistic knowledge on the interaction between SARS-CoV-2 infection and chemical exposures using an in silico approach, where we identified genes and molecular pathways affected by both chemical exposures and SARS-CoV-2 in human immune cells (T-cells, B-cells, NK-cells, dendritic, and monocyte cells). Our findings demonstrate for the first time that overlapping molecular mechanisms affected by a broad range of chemical exposures and COVID-19 are linked to IFN type I/II signaling pathways and the process of antigen presentation. Based on our data, we also predict that exposures to various chemical compounds will predominantly impact the population of monocytes during the response against COVID-19.


Subject(s)
COVID-19/immunology , Immunity, Innate/drug effects , Xenobiotics/pharmacology , B-Lymphocytes/cytology , B-Lymphocytes/drug effects , B-Lymphocytes/metabolism , COVID-19/pathology , COVID-19/virology , Humans , Interferons/metabolism , SARS-CoV-2/isolation & purification , Signal Transduction/drug effects , T-Lymphocytes/cytology , T-Lymphocytes/drug effects , T-Lymphocytes/metabolism
12.
J Exp Med ; 219(1)2022 01 03.
Article in English | MEDLINE | ID: covidwho-1510855

ABSTRACT

As SARS-CoV-2 continues to cause morbidity and mortality around the world, there is an urgent need for the development of effective medical countermeasures. Here, we assessed the antiviral capacity of a minimal RIG-I agonist, stem-loop RNA 14 (SLR14), in viral control, disease prevention, post-infection therapy, and cross-variant protection in mouse models of SARS-CoV-2 infection. A single dose of SLR14 prevented viral infection in the lower respiratory tract and development of severe disease in a type I interferon (IFN-I)-dependent manner. SLR14 demonstrated remarkable prophylactic protective capacity against lethal SARS-CoV-2 infection and retained considerable efficacy as a therapeutic agent. In immunodeficient mice carrying chronic SARS-CoV-2 infection, SLR14 elicited near-sterilizing innate immunity in the absence of the adaptive immune system. In the context of infection with variants of concern (VOCs), SLR14 conferred broad protection against emerging VOCs. These findings demonstrate the therapeutic potential of SLR14 as a host-directed, broad-spectrum antiviral for early post-exposure treatment and treatment of chronically infected immunosuppressed patients.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , RNA/metabolism , SARS-CoV-2/drug effects , Animals , COVID-19/metabolism , Disease Models, Animal , Immunity, Innate/drug effects , Interferon Type I/metabolism , Mice , Mice, Inbred BALB C
13.
Elife ; 102021 04 27.
Article in English | MEDLINE | ID: covidwho-1513055

ABSTRACT

Dendritic cells (DCs) regulate processes ranging from antitumor and antiviral immunity to host-microbe communication at mucosal surfaces. It remains difficult, however, to genetically manipulate human DCs, limiting our ability to probe how DCs elicit specific immune responses. Here, we develop a CRISPR-Cas9 genome editing method for human monocyte-derived DCs (moDCs) that mediates knockouts with a median efficiency of >94% across >300 genes. Using this method, we perform genetic screens in moDCs, identifying mechanisms by which DCs tune responses to lipopolysaccharides from the human microbiome. In addition, we reveal donor-specific responses to lipopolysaccharides, underscoring the importance of assessing immune phenotypes in donor-derived cells, and identify candidate genes that control this specificity, highlighting the potential of our method to pinpoint determinants of inter-individual variation in immunity. Our work sets the stage for a systematic dissection of the immune signaling at the host-microbiome interface and for targeted engineering of DCs for neoantigen vaccination.


Subject(s)
CRISPR-Associated Protein 9/genetics , CRISPR-Cas Systems , Clustered Regularly Interspaced Short Palindromic Repeats , Dendritic Cells/immunology , Gene Editing , Genomics , Immunity, Innate/genetics , Bacteroides thetaiotaomicron/immunology , CRISPR-Associated Protein 9/metabolism , Cells, Cultured , Cytokines/genetics , Cytokines/metabolism , Dendritic Cells/drug effects , Dendritic Cells/metabolism , Gene Expression Regulation , Humans , Immunity, Innate/drug effects , Lipopolysaccharides/pharmacology , Phenotype , Signal Transduction , Toll-Like Receptor 4/agonists , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism
14.
Mol Syst Biol ; 17(10): e10387, 2021 10.
Article in English | MEDLINE | ID: covidwho-1478718

ABSTRACT

We need to effectively combine the knowledge from surging literature with complex datasets to propose mechanistic models of SARS-CoV-2 infection, improving data interpretation and predicting key targets of intervention. Here, we describe a large-scale community effort to build an open access, interoperable and computable repository of COVID-19 molecular mechanisms. The COVID-19 Disease Map (C19DMap) is a graphical, interactive representation of disease-relevant molecular mechanisms linking many knowledge sources. Notably, it is a computational resource for graph-based analyses and disease modelling. To this end, we established a framework of tools, platforms and guidelines necessary for a multifaceted community of biocurators, domain experts, bioinformaticians and computational biologists. The diagrams of the C19DMap, curated from the literature, are integrated with relevant interaction and text mining databases. We demonstrate the application of network analysis and modelling approaches by concrete examples to highlight new testable hypotheses. This framework helps to find signatures of SARS-CoV-2 predisposition, treatment response or prioritisation of drug candidates. Such an approach may help deal with new waves of COVID-19 or similar pandemics in the long-term perspective.


Subject(s)
COVID-19/immunology , Computational Biology/methods , Databases, Factual , SARS-CoV-2/immunology , Software , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/genetics , COVID-19/virology , Computer Graphics , Cytokines/genetics , Cytokines/immunology , Data Mining/statistics & numerical data , Gene Expression Regulation , Host Microbial Interactions/genetics , Host Microbial Interactions/immunology , Humans , Immunity, Cellular/drug effects , Immunity, Humoral/drug effects , Immunity, Innate/drug effects , Lymphocytes/drug effects , Lymphocytes/immunology , Lymphocytes/virology , Metabolic Networks and Pathways/genetics , Metabolic Networks and Pathways/immunology , Myeloid Cells/drug effects , Myeloid Cells/immunology , Myeloid Cells/virology , Protein Interaction Mapping , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Signal Transduction , Transcription Factors/genetics , Transcription Factors/immunology , Viral Proteins/genetics , Viral Proteins/immunology
15.
Int J Mol Sci ; 22(19)2021 Sep 29.
Article in English | MEDLINE | ID: covidwho-1444231

ABSTRACT

The novel coronavirus severe acute respiratory syndrome (SARS-CoV-2) has progressed rapidly from an outbreak to a global pandemic, with new variants rapidly emerging. Coronavirus disease 2019 (COVID-19), the disease resulting from SARS-CoV-2 infection, can lead to multiorgan damage. Due to the extremely contagious and fatal nature of the virus, it has been a priority of medical research to find effective means of treatment. Amid this search, the role of vitamin D in modulating various aspects of the innate and adaptive immune system has been discussed. This review aims to consolidate the research surrounding the role of vitamin D in the treatment and prevention of COVID-19. While there are some conflicting results reported, the consensus is that vitamin D has a host of immunomodulatory effects which may be beneficial in the context of COVID-19 and that low levels of vitamin D can result in dysfunction of crucial antimicrobial effects, potentially contributing to poor prognosis. Studies also show that the effects of low vitamin D can be mitigated via supplementation, although the benefits of vitamin D supplementation in the treatment of COVID-19 remain controversial.


Subject(s)
COVID-19/prevention & control , Immunologic Factors/therapeutic use , Vitamin D/therapeutic use , Vitamins/therapeutic use , Adaptive Immunity/drug effects , Animals , COVID-19/immunology , Humans , Immunity, Innate/drug effects , Immunologic Factors/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , Vitamin D/pharmacology , Vitamins/pharmacology
16.
Molecules ; 26(19)2021 Sep 25.
Article in English | MEDLINE | ID: covidwho-1438675

ABSTRACT

The COVID-19 pandemic is caused by SARS-CoV-2 and is leading to the worst health crisis of this century. It emerged in China during late 2019 and rapidly spread all over the world, producing a broad spectrum of clinical disease severity, ranging from asymptomatic infection to death (4.3 million victims so far). Consequently, the scientific research is devoted to investigating the mechanisms of COVID-19 pathogenesis to both identify specific therapeutic drugs and develop vaccines. Although immunological mechanisms driving COVID-19 pathogenesis are still largely unknown, new understanding has emerged about the innate and adaptive immune responses elicited in SARS-CoV-2 infection, which are mainly focused on the dysregulated inflammatory response in severe COVID-19. Polyphenols are naturally occurring products with immunomodulatory activity, playing a relevant role in reducing inflammation and preventing the onset of serious chronic diseases. Mainly based on data collected before the appearance of SARS-CoV-2, polyphenols have been recently suggested as promising agents to fight COVID-19, and some clinical trials have already been approved with polyphenols to treat COVID-19. The aim of this review is to analyze and discuss the in vitro and in vivo research on the immunomodulatory activity of quercetin as a research model of polyphenols, focusing on research that addresses issues related to the dysregulated immune response in severe COVID-19. From this analysis, it emerges that although encouraging data are present, they are still insufficient to recommend polyphenols as potential immunomodulatory agents against COVID-19.


Subject(s)
COVID-19/drug therapy , Immunologic Factors/therapeutic use , Polyphenols/therapeutic use , Quercetin/therapeutic use , SARS-CoV-2/drug effects , Adaptive Immunity/drug effects , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/immunology , Humans , Immunity, Innate/drug effects , Immunologic Factors/chemistry , Immunologic Factors/pharmacology , Polyphenols/chemistry , Polyphenols/pharmacology , Quercetin/analogs & derivatives , Quercetin/pharmacology , SARS-CoV-2/immunology
17.
J Virol ; 95(24): e0117421, 2021 11 23.
Article in English | MEDLINE | ID: covidwho-1434894

ABSTRACT

Defective interfering particles (DIPs) of influenza A virus (IAV) are naturally occurring mutants that have an internal deletion in one of their eight viral RNA (vRNA) segments, rendering them propagation-incompetent. Upon coinfection with infectious standard virus (STV), DIPs interfere with STV replication through competitive inhibition. Thus, DIPs are proposed as potent antivirals for treatment of the influenza disease. To select corresponding candidates, we studied de novo generation of DIPs and propagation competition between different defective interfering (DI) vRNAs in an STV coinfection scenario in cell culture. A small-scale two-stage cultivation system that allows long-term semi-continuous propagation of IAV and its DIPs was used. Strong periodic oscillations in virus titers were observed due to the dynamic interaction of DIPs and STVs. Using next-generation sequencing, we detected a predominant formation and accumulation of DI vRNAs on the polymerase-encoding segments. Short DI vRNAs accumulated to higher fractions than longer ones, indicating a replication advantage, yet an optimum fragment length was observed. Some DI vRNAs showed breaking points in a specific part of their bundling signal (belonging to the packaging signal), suggesting its dispensability for DI vRNA propagation. Over a total cultivation time of 21 days, several individual DI vRNAs accumulated to high fractions, while others decreased. Using reverse genetics for IAV, purely clonal DIPs derived from highly replicating DI vRNAs were generated. We confirm that these DIPs exhibit a superior in vitro interfering efficacy compared to DIPs derived from lowly accumulated DI vRNAs and suggest promising candidates for efficacious antiviral treatment. IMPORTANCE Defective interfering particles (DIPs) emerge naturally during viral infection and typically show an internal deletion in the viral genome. Thus, DIPs are propagation-incompetent. Previous research suggests DIPs as potent antiviral compounds for many different virus families due to their ability to interfere with virus replication by competitive inhibition. For instance, the administration of influenza A virus (IAV) DIPs resulted in a rescue of mice from an otherwise lethal IAV dose. Moreover, no apparent toxic effects were observed when only DIPs were administered to mice and ferrets. IAV DIPs show antiviral activity against many different IAV strains, including pandemic and highly pathogenic avian strains, and even against nonhomologous viruses, such as SARS-CoV-2, by stimulation of innate immunity. Here, we used a cultivation/infection system, which exerted selection pressure toward accumulation of highly competitive IAV DIPs. These DIPs showed a superior interfering efficacy in vitro, and we suggest them for effective antiviral therapy.


Subject(s)
Antiviral Agents/pharmacology , Drug Design/methods , Influenza A virus , Influenza, Human/virology , RNA, Viral , Animals , Cell Culture Techniques , Cell Line , Defective Viruses/genetics , Dogs , Gene Deletion , Genome, Viral , Humans , Immunity, Innate/drug effects , Madin Darby Canine Kidney Cells , Oscillometry , Real-Time Polymerase Chain Reaction , Viral Load/drug effects , Virus Replication/drug effects
18.
Molecules ; 25(12)2020 Jun 26.
Article in English | MEDLINE | ID: covidwho-1389454

ABSTRACT

Viruses can be spread from one person to another; therefore, they may cause disorders in many people, sometimes leading to epidemics and even pandemics. New, previously unstudied viruses and some specific mutant or recombinant variants of known viruses constantly appear. An example is a variant of coronaviruses (CoV) causing severe acute respiratory syndrome (SARS), named SARS-CoV-2. Some antiviral drugs, such as remdesivir as well as antiretroviral drugs including darunavir, lopinavir, and ritonavir are suggested to be effective in treating disorders caused by SARS-CoV-2. There are data on the utilization of antiretroviral drugs against SARS-CoV-2. Since there are many studies aimed at the identification of the molecular mechanisms of human immunodeficiency virus type 1 (HIV-1) infection and the development of novel therapeutic approaches against HIV-1, we used HIV-1 for our case study to identify possible molecular pathways shared by SARS-CoV-2 and HIV-1. We applied a text and data mining workflow and identified a list of 46 targets, which can be essential for the development of infections caused by SARS-CoV-2 and HIV-1. We show that SARS-CoV-2 and HIV-1 share some molecular pathways involved in inflammation, immune response, cell cycle regulation.


Subject(s)
Coronavirus Infections/epidemiology , Coronavirus Infections/metabolism , Data Mining/methods , HIV Infections/epidemiology , HIV Infections/metabolism , Host-Pathogen Interactions/immunology , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/metabolism , Anti-Inflammatory Agents/therapeutic use , Antigens, Differentiation/genetics , Antigens, Differentiation/immunology , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , COVID-19 , Complement System Proteins/genetics , Complement System Proteins/immunology , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Databases, Genetic , Gene Expression Regulation , HIV Infections/drug therapy , HIV Infections/immunology , HIV-1/drug effects , HIV-1/immunology , HIV-1/pathogenicity , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/genetics , Humans , Immunity, Innate/drug effects , Immunologic Factors/therapeutic use , Inflammation , Interferons/genetics , Interferons/immunology , Interleukins/genetics , Interleukins/immunology , Metabolic Networks and Pathways/drug effects , Metabolic Networks and Pathways/genetics , Metabolic Networks and Pathways/immunology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Repressor Proteins/genetics , Repressor Proteins/immunology , SARS-CoV-2 , Signal Transduction , Toll-Like Receptors/genetics , Toll-Like Receptors/immunology , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/immunology
19.
Front Immunol ; 11: 631743, 2020.
Article in English | MEDLINE | ID: covidwho-1389175

ABSTRACT

The concept of trained immunity has recently emerged as a mechanism contributing to several immune mediated inflammatory conditions. Trained immunity is defined by the immunological memory developed in innate immune cells after a primary non-specific stimulus that, in turn, promotes a heightened inflammatory response upon a secondary challenge. The most characteristic changes associated to this process involve the rewiring of cell metabolism and epigenetic reprogramming. Under physiological conditions, the role of trained immune cells ensures a prompt response. This action is limited by effective resolution of inflammation and tissue repair in order to restore homeostasis. However, unrestrained activation of innate immune cells contributes to the development of chronic inflammation and tissue destruction through the secretion of inflammatory cytokines, proteases and growth factors. Therefore, interventions aimed at reversing the changes induced by trained immunity provide potential therapeutic approaches to treat inflammatory and autoimmune diseases like rheumatoid arthritis (RA). We review cellular approaches that target metabolism and the epigenetic reprogramming of dendritic cells, macrophages, natural killer cells, and other trained cells in the context of autoimmune inflammatory diseases.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Autoimmune Diseases/drug therapy , Autoimmunity/drug effects , Biological Products/therapeutic use , Immune System/drug effects , Inflammation/drug therapy , Animals , Autoimmune Diseases/genetics , Autoimmune Diseases/immunology , Autoimmune Diseases/metabolism , COVID-19/drug therapy , COVID-19/immunology , Energy Metabolism/drug effects , Epigenesis, Genetic/drug effects , Humans , Immune System/immunology , Immune System/metabolism , Immunity, Innate/drug effects , Immunologic Memory/drug effects , Inflammation/genetics , Inflammation/immunology , Inflammation/metabolism , Signal Transduction
20.
Cell ; 181(5): 969-977, 2020 05 28.
Article in English | MEDLINE | ID: covidwho-1385208

ABSTRACT

SARS-CoV-2 infection is mild in the majority of individuals but progresses into severe pneumonia in a small proportion of patients. The increased susceptibility to severe disease in the elderly and individuals with co-morbidities argues for an initial defect in anti-viral host defense mechanisms. Long-term boosting of innate immune responses, also termed "trained immunity," by certain live vaccines (BCG, oral polio vaccine, measles) induces heterologous protection against infections through epigenetic, transcriptional, and functional reprogramming of innate immune cells. We propose that induction of trained immunity by whole-microorganism vaccines may represent an important tool for reducing susceptibility to and severity of SARS-CoV-2.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/immunology , Immunity, Innate , Immunomodulation , Pneumonia, Viral/immunology , SARS Virus/physiology , Animals , BCG Vaccine/immunology , COVID-19 , Clinical Trials as Topic , Coronavirus Infections/pathology , Coronavirus Infections/physiopathology , Coronavirus Infections/transmission , Humans , Immunity, Innate/drug effects , Lung/immunology , Lung/pathology , Lymphopenia/pathology , Middle East Respiratory Syndrome Coronavirus/physiology , Pandemics , Pneumonia, Viral/pathology , Pneumonia, Viral/physiopathology , Pneumonia, Viral/transmission , SARS-CoV-2 , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/pathology , Virus Replication
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