Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 38
Filter
1.
Immunity ; 54(12): 2673-2675, 2021 Dec 14.
Article in English | MEDLINE | ID: covidwho-1709840

ABSTRACT

We talk to first and last authors Katalin Karikó and Drew Weissman about their seminal 2005 paper ''Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA", about how they see the work in retrospect, the current progress in the field, and their inspiration-then and now.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , RNA/immunology , SARS-CoV-2/physiology , Toll-Like Receptors/metabolism , /immunology , Access to Information , Animals , Humans , Information Dissemination , Mice , Nucleosides/immunology
2.
Nat Immunol ; 23(2): 165-176, 2022 02.
Article in English | MEDLINE | ID: covidwho-1671597

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2, continues to cause substantial morbidity and mortality. While most infections are mild, some patients experience severe and potentially fatal systemic inflammation, tissue damage, cytokine storm and acute respiratory distress syndrome. The innate immune system acts as the first line of defense, sensing the virus through pattern recognition receptors and activating inflammatory pathways that promote viral clearance. Here, we discuss innate immune processes involved in SARS-CoV-2 recognition and the resultant inflammation. Improved understanding of how the innate immune system detects and responds to SARS-CoV-2 will help identify targeted therapeutic modalities that mitigate severe disease and improve patient outcomes.


Subject(s)
COVID-19/immunology , Immunity, Innate , SARS-CoV-2/immunology , Animals , COVID-19/metabolism , COVID-19/virology , Cytokines/immunology , Cytokines/metabolism , Humans , Immune Evasion , Inflammasomes/immunology , Inflammasomes/metabolism , NLR Proteins/immunology , NLR Proteins/metabolism , Receptors, Pattern Recognition/immunology , Receptors, Pattern Recognition/metabolism , SARS-CoV-2/pathogenicity , Signal Transduction , Toll-Like Receptors/immunology , Toll-Like Receptors/metabolism , Virus Internalization
3.
Gastroenterology ; 160(3): 925-928.e4, 2021 02.
Article in English | MEDLINE | ID: covidwho-1575253
4.
Viruses ; 13(11)2021 11 18.
Article in English | MEDLINE | ID: covidwho-1524175

ABSTRACT

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to coronavirus disease (COVID-19), a global health pandemic causing millions of deaths worldwide. However, the immunopathogenesis of COVID-19, particularly the interaction between SARS-CoV-2 and host innate immunity, remains unclear. The innate immune system acts as the first line of host defense, which is critical for the initial detection of invading pathogens and the activation and shaping of adaptive immunity. Toll-like receptors (TLRs) are key sensors of innate immunity that recognize pathogen-associated molecular patterns and activate downstream signaling for pro-inflammatory cytokine and chemokine production. However, TLRs may also act as a double-edged sword, and dysregulated TLR responses may enhance immune-mediated pathology, instead of providing protection. Therefore, a proper understanding of the interaction between TLRs and SARS-CoV-2 is of great importance for devising therapeutic and preventive strategies. The use of TLR agonists as vaccine adjuvants for human disease is a promising approach that could be applied in the investigation of COVID-19 vaccines. In this review, we discuss the recent progress in our understanding of host innate immune responses in SARS-CoV-2 infection, with particular focus on TLR response. In addition, we discuss the use of TLR agonists as vaccine adjuvants in enhancing the efficacy of COVID-19 vaccine.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , Toll-Like Receptors/agonists , Toll-Like Receptors/immunology , Animals , Humans , SARS-CoV-2/immunology , Toll-Like Receptors/metabolism
5.
Innate Immun ; 27(7-8): 503-513, 2021 10.
Article in English | MEDLINE | ID: covidwho-1523254

ABSTRACT

COVID-19 is both a viral illness and a disease of immunopathology. Proximal events within the innate immune system drive the balance between deleterious inflammation and viral clearance. We hypothesize that a divergence between the generation of excessive inflammation through over activation of the TLR associated myeloid differentiation primary response (MyD88) pathway relative to the TIR-domain-containing adaptor-inducing IFN-ß (TRIF) pathway plays a key role in COVID-19 severity. Both viral elements and damage associated host molecules act as TLR ligands in this process. In this review, we detail the mechanism for this imbalance in COVID-19 based on available evidence, and we discuss how modulation of critical elements may be important in reducing severity of disease.


Subject(s)
COVID-19/metabolism , COVID-19/pathology , Toll-Like Receptors/drug effects , Toll-Like Receptors/metabolism , Animals , COVID-19/immunology , Humans , Immunity, Innate , Signal Transduction/drug effects
6.
Immunology ; 164(4): 722-736, 2021 12.
Article in English | MEDLINE | ID: covidwho-1494730

ABSTRACT

Bruton's tyrosine kinase (BTK) is a TEC kinase with a multifaceted role in B-cell biology and function, highlighted by its position as a critical component of the B-cell receptor signalling pathway. Due to its role as a therapeutic target in several haematological malignancies including chronic lymphocytic leukaemia, BTK has been gaining tremendous momentum in recent years. Within the immune system, BTK plays a part in numerous pathways and cells beyond B cells (i.e. T cells, macrophages). Not surprisingly, BTK has been elucidated to be a driving factor not only in lymphoproliferative disorders but also in autoimmune diseases and response to infection. To extort this role, BTK inhibitors such as ibrutinib have been developed to target BTK in other diseases. However, due to rising levels of resistance, the urgency to develop new inhibitors with alternative modes of targeting BTK is high. To meet this demand, an expanding list of BTK inhibitors is currently being trialled. In this review, we synopsize recent discoveries regarding BTK and its role within different immune cells and pathways. Additionally, we discuss the broad significance and relevance of BTK for various diseases ranging from haematology and rheumatology to the COVID-19 pandemic. Overall, BTK signalling and its targetable nature have emerged as immensely important for a wide range of clinical applications. The development of novel, more specific and less toxic BTK inhibitors could be revolutionary for a significant number of diseases with yet unmet treatment needs.


Subject(s)
Agammaglobulinaemia Tyrosine Kinase/metabolism , B-Lymphocytes/enzymology , Immune System/enzymology , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Animals , Autoimmune Diseases/drug therapy , Autoimmune Diseases/enzymology , Autoimmune Diseases/immunology , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , COVID-19/drug therapy , COVID-19/enzymology , COVID-19/immunology , Humans , Immune System/drug effects , Immune System/immunology , Lymphoproliferative Disorders/drug therapy , Lymphoproliferative Disorders/enzymology , Lymphoproliferative Disorders/immunology , Molecular Targeted Therapy , Protein Kinase Inhibitors/therapeutic use , Receptors, Antigen, B-Cell/metabolism , Receptors, Chemokine/metabolism , Signal Transduction , Toll-Like Receptors/metabolism
7.
Viruses ; 13(11)2021 10 22.
Article in English | MEDLINE | ID: covidwho-1481020

ABSTRACT

The global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection, threatens the entire world. It has affected every aspect of life and increased the burden on both healthcare and socioeconomic systems. Current studies have revealed that excessive inflammatory immune responses are responsible for the severity of COVID-19, which suggests that anti-inflammatory drugs may be promising therapeutic treatments. However, there are currently a limited number of approved therapeutics for COVID-19. Toll-like receptors (TLRs), which recognize microbial components derived from invading pathogens, are involved in both the initiation of innate responses against SARS-CoV-2 infection and the hyperinflammatory phenotype of COVID-19. In this review, we provide current knowledge on the pivotal role of TLRs in immune responses against SARS-CoV-2 infection and demonstrate the potential effectiveness of TLR-targeting drugs on the control of hyperinflammation in patients with COVID-19.


Subject(s)
COVID-19/immunology , Immunity, Innate , SARS-CoV-2/immunology , Toll-Like Receptors/immunology , Animals , Anti-Inflammatory Agents/therapeutic use , COVID-19/complications , COVID-19/drug therapy , COVID-19/virology , Cytokine Release Syndrome , Humans , SARS-CoV-2/physiology , Severity of Illness Index , Systemic Inflammatory Response Syndrome/complications , Systemic Inflammatory Response Syndrome/drug therapy , Toll-Like Receptors/antagonists & inhibitors , Toll-Like Receptors/metabolism
8.
Nutrients ; 13(8)2021 Jul 27.
Article in English | MEDLINE | ID: covidwho-1430928

ABSTRACT

Gut microbiota has emerged as a major metabolically active organ with critical functions in both health and disease. The trillions of microorganisms hosted by the gastrointestinal tract are involved in numerous physiological and metabolic processes including modulation of appetite and regulation of energy in the host spanning from periphery to the brain. Indeed, bacteria and their metabolic byproducts are working in concert with the host chemosensory signaling pathways to affect both short- and long-term ingestive behavior. Sensing of nutrients and taste by specialized G protein-coupled receptor cells is important in transmitting food-related signals, optimizing nutrition as well as in prevention and treatment of several diseases, notably obesity, diabetes and associated metabolic disorders. Further, bacteria metabolites interact with specialized receptors cells expressed by gut epithelium leading to taste and appetite response changes to nutrients. This review describes recent advances on the role of gut bacteria in taste perception and functions. It further discusses how intestinal dysbiosis characteristic of several pathological conditions may alter and modulate taste preference and food consumption via changes in taste receptor expression.


Subject(s)
Bacterial Physiological Phenomena , Gastrointestinal Microbiome/physiology , Intestines/microbiology , Taste Perception , Animals , Antineoplastic Agents/therapeutic use , Bariatric Surgery , COVID-19/physiopathology , Diet , Dysbiosis/physiopathology , Feeding Behavior , Hormones/metabolism , Humans , Inflammatory Bowel Diseases/physiopathology , Neoplasms/drug therapy , Neoplasms/physiopathology , Receptors, G-Protein-Coupled/metabolism , Taste , Taste Buds/physiology , Toll-Like Receptors/metabolism
9.
Immunology ; 164(4): 722-736, 2021 12.
Article in English | MEDLINE | ID: covidwho-1429802

ABSTRACT

Bruton's tyrosine kinase (BTK) is a TEC kinase with a multifaceted role in B-cell biology and function, highlighted by its position as a critical component of the B-cell receptor signalling pathway. Due to its role as a therapeutic target in several haematological malignancies including chronic lymphocytic leukaemia, BTK has been gaining tremendous momentum in recent years. Within the immune system, BTK plays a part in numerous pathways and cells beyond B cells (i.e. T cells, macrophages). Not surprisingly, BTK has been elucidated to be a driving factor not only in lymphoproliferative disorders but also in autoimmune diseases and response to infection. To extort this role, BTK inhibitors such as ibrutinib have been developed to target BTK in other diseases. However, due to rising levels of resistance, the urgency to develop new inhibitors with alternative modes of targeting BTK is high. To meet this demand, an expanding list of BTK inhibitors is currently being trialled. In this review, we synopsize recent discoveries regarding BTK and its role within different immune cells and pathways. Additionally, we discuss the broad significance and relevance of BTK for various diseases ranging from haematology and rheumatology to the COVID-19 pandemic. Overall, BTK signalling and its targetable nature have emerged as immensely important for a wide range of clinical applications. The development of novel, more specific and less toxic BTK inhibitors could be revolutionary for a significant number of diseases with yet unmet treatment needs.


Subject(s)
Agammaglobulinaemia Tyrosine Kinase/metabolism , B-Lymphocytes/enzymology , Immune System/enzymology , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Animals , Autoimmune Diseases/drug therapy , Autoimmune Diseases/enzymology , Autoimmune Diseases/immunology , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , COVID-19/drug therapy , COVID-19/enzymology , COVID-19/immunology , Humans , Immune System/drug effects , Immune System/immunology , Lymphoproliferative Disorders/drug therapy , Lymphoproliferative Disorders/enzymology , Lymphoproliferative Disorders/immunology , Molecular Targeted Therapy , Protein Kinase Inhibitors/therapeutic use , Receptors, Antigen, B-Cell/metabolism , Receptors, Chemokine/metabolism , Signal Transduction , Toll-Like Receptors/metabolism
10.
Cell Biochem Funct ; 39(8): 945-954, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1427069

ABSTRACT

New coronavirus disease 2019 (COVID-19), as a pandemic disaster, has drawn the attention of researchers in various fields to discover suitable therapeutic approaches for the management of COVID-19 patients. Currently, there are many worries about the rapid spread of COVID-19; there is no approved treatment for this infectious disease, despite many efforts to develop therapeutic procedures for COVID-19. Emerging evidence shows that mesenchymal stromal/stem cell (MSC) therapy can be a suitable option for the management of COVID-19. These cells have many biological features (including the potential of differentiation, high safety and effectiveness, secretion of trophic factors and immunoregulatory features) that make them suitable for the treatment of various diseases. However, some studies have questioned the positive role of MSC therapy in the treatment of COVID-19. Accordingly, in this paper, we will focus on the therapeutic impacts of MSCs and their critical role in cytokine storm of COVID-19 patients.


Subject(s)
COVID-19/therapy , Mesenchymal Stem Cell Transplantation , COVID-19/pathology , COVID-19/virology , Cell Communication , Cytokine Release Syndrome/pathology , Humans , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/metabolism , SARS-CoV-2/isolation & purification , Toll-Like Receptors/metabolism
11.
Viruses ; 13(9)2021 09 15.
Article in English | MEDLINE | ID: covidwho-1411083

ABSTRACT

Type I Interferons (IFN-I) are a family of potent antiviral cytokines that act through the direct restriction of viral replication and by enhancing antiviral immunity. However, these powerful cytokines are a caged lion, as excessive and sustained IFN-I production can drive immunopathology during infection, and aberrant IFN-I production is a feature of several types of autoimmunity. As specialized producers of IFN-I plasmacytoid (p), dendritic cells (DCs) can secrete superb quantities and a wide breadth of IFN-I isoforms immediately after infection or stimulation, and are the focus of this review. Notably, a few days after viral infection pDCs tune down their capacity for IFN-I production, producing less cytokines in response to both the ongoing infection and unrelated secondary stimulations. This process, hereby referred to as "pDC exhaustion", favors viral persistence and associates with reduced innate responses and increased susceptibility to secondary opportunistic infections. On the other hand, pDC exhaustion may be a compromise to avoid IFN-I driven immunopathology. In this review we reflect on the mechanisms that initially induce IFN-I and subsequently silence their production by pDCs during a viral infection. While these processes have been long studied across numerous viral infection models, the 2019 coronavirus disease (COVID-19) pandemic has brought their discussion back to the fore, and so we also discuss emerging results related to pDC-IFN-I production in the context of COVID-19.


Subject(s)
COVID-19/metabolism , COVID-19/virology , Host-Pathogen Interactions , Interferon Type I/biosynthesis , SARS-CoV-2/physiology , Biomarkers , COVID-19/immunology , Cytokines/metabolism , Dendritic Cells/immunology , Dendritic Cells/metabolism , Host-Pathogen Interactions/immunology , Humans , Immunity, Innate/immunology , Immunomodulation , Toll-Like Receptors/metabolism
12.
Curr Opin Immunol ; 73: 9-15, 2021 12.
Article in English | MEDLINE | ID: covidwho-1355579

ABSTRACT

During microbial infection, macrophages link recognition of microbial stimuli to the induction of Type I inflammatory responses. Such inflammatory responses coordinate host defense and pathogen elimination but induce significant tissue damage if sustained, so macrophages are initially activated to induce inflammatory responses but then shift to a tolerant state to suppress inflammatory responses. Macrophage tolerance is regulated by induction of negative regulators of TLR signaling, but its metabolic basis was not known. Here, we review recent studies that indicate that macrophage metabolism changes dynamically over the course of microbial exposure to influence a shift in the inflammatory response. In particular, an initial increase in oxidative metabolism boosts the induction of inflammatory responses, but is followed by a shutdown of oxidative metabolism that contributes to suppression of inflammatory responses. We propose a unifying model for how dynamic changes to oxidative metabolism influences regulation of macrophage inflammatory responses during microbial exposure.


Subject(s)
Inflammation/immunology , Macrophages/metabolism , Oxidative Stress/immunology , Animals , Humans , Immune Tolerance , Immunomodulation , Macrophages/immunology , Models, Immunological , Oxidation-Reduction , Toll-Like Receptors/metabolism
13.
Int J Mol Sci ; 22(15)2021 Jul 23.
Article in English | MEDLINE | ID: covidwho-1346497

ABSTRACT

Platelets are hematopoietic cells whose main function has for a long time been considered to be the maintenance of vascular integrity. They have an essential role in the hemostatic response, but they also have functional capabilities that go far beyond it. This review will provide an overview of platelet functions. Indeed, stress signals may induce platelet apoptosis through proapoptotis or hemostasis receptors, necrosis, and even autophagy. Platelets also interact with immune cells and modulate immune responses in terms of activation, maturation, recruitment and cytokine secretion. This review will also show that platelets, thanks to their wide range of innate immune receptors, and in particular toll-like receptors, and can be considered sentinels actively participating in the immuno-surveillance of the body. We will discuss the diversity of platelet responses following the engagement of these receptors as well as the signaling pathways involved. Finally, we will show that while platelets contribute significantly, via their TLRs, to immune response and inflammation, these receptors also participate in the pathophysiological processes associated with various pathogens and diseases, including cancer and atherosclerosis.


Subject(s)
Atherosclerosis/pathology , Blood Platelets/pathology , Immunity, Innate/immunology , Neoplasms/pathology , Platelet Activation , Receptors, Immunologic/metabolism , Toll-Like Receptors/metabolism , Animals , Atherosclerosis/immunology , Atherosclerosis/metabolism , Blood Platelets/immunology , Blood Platelets/metabolism , Humans , Neoplasms/immunology , Neoplasms/metabolism
14.
Int J Mol Sci ; 22(15)2021 Jul 28.
Article in English | MEDLINE | ID: covidwho-1335097

ABSTRACT

Different mechanisms were proposed as responsible for COVID-19 neurological symptoms but a clear one has not been established yet. In this work we aimed to study SARS-CoV-2 capacity to infect pediatric human cortical neuronal HCN-2 cells, studying the changes in the transcriptomic profile by next generation sequencing. SARS-CoV-2 was able to replicate in HCN-2 cells, that did not express ACE2, confirmed also with Western blot, and TMPRSS2. Looking for pattern recognition receptor expression, we found the deregulation of scavenger receptors, such as SR-B1, and the downregulation of genes encoding for Nod-like receptors. On the other hand, TLR1, TLR4 and TLR6 encoding for Toll-like receptors (TLRs) were upregulated. We also found the upregulation of genes encoding for ERK, JNK, NF-κB and Caspase 8 in our transcriptomic analysis. Regarding the expression of known receptors for viral RNA, only RIG-1 showed an increased expression; downstream RIG-1, the genes encoding for TRAF3, IKKε and IRF3 were downregulated. We also found the upregulation of genes encoding for chemokines and accordingly we found an increase in cytokine/chemokine levels in the medium. According to our results, it is possible to speculate that additionally to ACE2 and TMPRSS2, also other receptors may interact with SARS-CoV-2 proteins and mediate its entry or pathogenesis in pediatric cortical neurons infected with SARS-CoV-2. In particular, TLRs signaling could be crucial for the neurological involvement related to SARS-CoV-2 infection.


Subject(s)
COVID-19/metabolism , Cerebral Cortex/metabolism , Neurons/virology , SARS-CoV-2/pathogenicity , Toll-Like Receptors/metabolism , COVID-19/genetics , COVID-19/immunology , Child , Cytokines/metabolism , Gene Expression Profiling , Gene Expression Regulation , Humans , Neurons/immunology , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , Signal Transduction/genetics , Toll-Like Receptors/genetics , Virus Replication
15.
Pharmacol Res ; 157: 104820, 2020 07.
Article in English | MEDLINE | ID: covidwho-1318923

ABSTRACT

The Coronavirus Disease 2019 (COVID-19) pandemic has become a huge threaten to global health, which raise urgent demand of developing efficient therapeutic strategy. The aim of the present study is to dissect the chemical composition and the pharmacological mechanism of Qingfei Paidu Decoction (QFPD), a clinically used Chinese medicine for treating COVID-19 patients in China. Through comprehensive analysis by liquid chromatography coupled with high resolution mass spectrometry (MS), a total of 129 compounds of QFPD were putatively identified. We also constructed molecular networking of mass spectrometry data to classify these compounds into 14 main clusters, in which exhibited specific patterns of flavonoids (45 %), glycosides (15 %), carboxylic acids (10 %), and saponins (5 %). The target network model of QFPD, established by predicting and collecting the targets of identified compounds, indicated a pivotal role of Ma Xing Shi Gan Decoction (MXSG) in the therapeutic efficacy of QFPD. Supportively, through transcriptomic analysis of gene expression after MXSG administration in rat model of LPS-induced pneumonia, the thrombin and Toll-like receptor (TLR) signaling pathway were suggested to be essential pathways for MXSG mediated anti-inflammatory effects. Besides, changes in content of major compounds in MXSG during decoction were found by the chemical analysis. We also validate that one major compound in MXSG, i.e. glycyrrhizic acid, inhibited TLR agonists induced IL-6 production in macrophage. In conclusion, the integration of in silico and experimental results indicated that the therapeutic effects of QFPD against COVID-19 may be attributed to the anti-inflammatory effects of MXSG, which supports the rationality of the compatibility of TCM.


Subject(s)
Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Drugs, Chinese Herbal/analysis , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic use , Pneumonia, Viral/drug therapy , Animals , Anti-Inflammatory Agents/analysis , Anti-Inflammatory Agents/pharmacology , COVID-19 , Cells, Cultured , Computer Simulation , Coronavirus Infections/genetics , Gene Expression/drug effects , Glycyrrhizic Acid/pharmacology , Humans , Interleukin-6/metabolism , Lipopeptides/antagonists & inhibitors , Lipopeptides/pharmacology , Lipopolysaccharides , Male , Pandemics , Pneumonia/chemically induced , Pneumonia/metabolism , Pneumonia, Viral/genetics , Rats , SARS-CoV-2 , Signal Transduction/drug effects , Thrombin/metabolism , Toll-Like Receptors/metabolism
16.
Cell ; 184(15): 3915-3935.e21, 2021 07 22.
Article in English | MEDLINE | ID: covidwho-1283262

ABSTRACT

Emerging evidence indicates a fundamental role for the epigenome in immunity. Here, we mapped the epigenomic and transcriptional landscape of immunity to influenza vaccination in humans at the single-cell level. Vaccination against seasonal influenza induced persistently diminished H3K27ac in monocytes and myeloid dendritic cells (mDCs), which was associated with impaired cytokine responses to Toll-like receptor stimulation. Single-cell ATAC-seq analysis revealed an epigenomically distinct subcluster of monocytes with reduced chromatin accessibility at AP-1-targeted loci after vaccination. Similar effects were observed in response to vaccination with the AS03-adjuvanted H5N1 pandemic influenza vaccine. However, this vaccine also stimulated persistently increased chromatin accessibility at interferon response factor (IRF) loci in monocytes and mDCs. This was associated with elevated expression of antiviral genes and heightened resistance to the unrelated Zika and Dengue viruses. These results demonstrate that vaccination stimulates persistent epigenomic remodeling of the innate immune system and reveal AS03's potential as an epigenetic adjuvant.


Subject(s)
Epigenomics , Immunity/genetics , Influenza Vaccines/genetics , Influenza Vaccines/immunology , Single-Cell Analysis , Transcription, Genetic , Vaccination , Adolescent , Adult , Anti-Bacterial Agents/pharmacology , Antigens, CD34/metabolism , Antiviral Agents/pharmacology , Cellular Reprogramming , Chromatin/metabolism , Cytokines/biosynthesis , Drug Combinations , Female , Gene Expression Regulation , Histones/metabolism , Humans , Immunity, Innate/genetics , Influenza A Virus, H5N1 Subtype/drug effects , Influenza A Virus, H5N1 Subtype/immunology , Interferon Type I/metabolism , Male , Myeloid Cells/metabolism , Polysorbates/pharmacology , Squalene/pharmacology , Toll-Like Receptors/metabolism , Transcription Factor AP-1/metabolism , Transcriptome/genetics , Young Adult , alpha-Tocopherol/pharmacology
18.
J Med Virol ; 93(4): 2476-2486, 2021 04.
Article in English | MEDLINE | ID: covidwho-1217395

ABSTRACT

The coronavirus disease-2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has already resulted in a huge setback to mankind in terms of millions of deaths, while the unavailability of an appropriate therapeutic strategy has made the scenario much more severe. Toll-like receptors (TLRs) are crucial mediators and regulators of host immunity and the role of human cell surface TLRs in SARS-CoV-2 induced inflammatory pathogenesis has been demonstrated recently. However, the functional significance of the human intracellular TLRs including TLR3, 7, 8, and 9 is yet unclear. Hitherto, the involvement of these intracellular TLRs in inducing pro-inflammatory responses in COVID-19 has been reported but the identity of the interacting viral RNA molecule(s) and the corresponding TLRs have not been explored. This study hopes to rationalize the comparative binding of the major SARS-CoV-2 mRNAs to the intracellular TLRs, considering the solvent-based force-fields operational in the cytosolic aqueous microenvironment that predominantly drives these interactions. Our in silico study on the binding of all mRNAs with the intracellular TLRs depicts that the mRNA of NSP10, S2, and E proteins of SARS-CoV-2 are possible virus-associated molecular patterns that bind to TLR3, TLR9, and TLR7, respectively, and trigger downstream cascade reactions. Intriguingly, binding of the viral mRNAs resulted in variable degrees of conformational changes in the ligand-binding domain of the TLRs ratifying the activation of the downstream inflammatory signaling cascade. Taken together, the current study is the maiden report to describe the role of TLR3, 7, and 9 in COVID-19 immunobiology and these could serve as useful targets for the conception of a therapeutic strategy against the pandemic.


Subject(s)
COVID-19/virology , RNA, Messenger/genetics , RNA, Viral/metabolism , SARS-CoV-2/metabolism , Toll-Like Receptors/metabolism , Binding Sites , COVID-19/immunology , COVID-19/metabolism , Computer Simulation , Genome, Viral , Humans , Molecular Docking Simulation , Protein Binding , RNA, Messenger/analysis , RNA, Messenger/metabolism , RNA, Viral/chemistry , RNA, Viral/genetics , SARS-CoV-2/genetics , Toll-Like Receptors/chemistry , Toll-Like Receptors/genetics
19.
Clin Immunol ; 227: 108727, 2021 06.
Article in English | MEDLINE | ID: covidwho-1193258

ABSTRACT

With the global spread of coronavirus disease 2019 (COVID-19), the important role of natural killer (NK) cells in the control of various viral infections attracted more interest, via non-specific activation, such as antibody-dependent cell-mediated cytotoxicity (ADCC) and activating receptors, as well as specific activation, such as memory-like NK generation. In response to different viral infections, NK cells fight viruses in different ways, and different NK subsets proliferate. For instance, cytomegalovirus (CMV) induces NKG2C + CD57 + KIR+ NK cells to expand 3-6 months after hematopoietic stem cell transplantation (HSCT), but human immunodeficiency virus (HIV) induces KIR3DS1+/KIR3DL1 NK cells to expand in the acute phase of infection. However, the similarities and differences among these processes and their molecular mechanisms have not been fully discussed. In this article, we provide a summary and comparison of antiviral mechanisms, unique subset expansion and time periods in peripheral blood and tissues under different conditions of CMV, HIV, Epstein-Barr virus (EBV), COVID-19 and hepatitis B virus (HBV) infections. Accordingly, we also discuss current clinical NK-associated antiviral applications, including cell therapy and NK-related biological agents, and we state the progress and future prospects of NK cell antiviral treatment.


Subject(s)
COVID-19/immunology , COVID-19/virology , Host Microbial Interactions/immunology , Killer Cells, Natural/immunology , Antibody-Dependent Cell Cytotoxicity , COVID-19/blood , Cytomegalovirus/immunology , Cytomegalovirus Infections/blood , Cytomegalovirus Infections/immunology , Cytomegalovirus Infections/virology , Epstein-Barr Virus Infections/blood , Epstein-Barr Virus Infections/immunology , Epstein-Barr Virus Infections/virology , HIV/immunology , HIV Infections/blood , HIV Infections/immunology , HIV Infections/virology , Hepatitis B/blood , Hepatitis B/immunology , Hepatitis B/virology , Hepatitis B virus/immunology , Herpesvirus 4, Human/immunology , Humans , SARS-CoV-2/immunology , Toll-Like Receptors/metabolism
20.
Front Immunol ; 12: 650331, 2021.
Article in English | MEDLINE | ID: covidwho-1156125

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection represents a global health crisis. Immune cell activation via pattern recognition receptors has been implicated as a driver of the hyperinflammatory response seen in COVID-19. However, our understanding of the specific immune responses to SARS-CoV-2 remains limited. Mast cells (MCs) and eosinophils are innate immune cells that play pathogenic roles in many inflammatory responses. Here we report MC-derived proteases and eosinophil-associated mediators are elevated in COVID-19 patient sera and lung tissues. Stimulation of viral-sensing toll-like receptors in vitro and administration of synthetic viral RNA in vivo induced features of hyperinflammation, including cytokine elevation, immune cell airway infiltration, and MC-protease production-effects suppressed by an anti-Siglec-8 monoclonal antibody which selectively inhibits MCs and depletes eosinophils. Similarly, anti-Siglec-8 treatment reduced disease severity and airway inflammation in a respiratory viral infection model. These results suggest that MC and eosinophil activation are associated with COVID-19 inflammation and anti-Siglec-8 antibodies are a potential therapeutic approach for attenuating excessive inflammation during viral infections.


Subject(s)
Antigens, CD/immunology , Antigens, Differentiation, B-Lymphocyte/immunology , COVID-19/immunology , Eosinophils/immunology , Lectins/immunology , Mast Cells/immunology , Respiratory Syncytial Virus Infections/immunology , Respiratory Syncytial Viruses/immunology , SARS-CoV-2/immunology , Toll-Like Receptors/immunology , Animals , Antibodies, Monoclonal/pharmacology , Antigens, CD/genetics , Antigens, CD/metabolism , Antigens, Differentiation, B-Lymphocyte/genetics , Antigens, Differentiation, B-Lymphocyte/metabolism , COVID-19/metabolism , COVID-19/prevention & control , COVID-19/virology , Case-Control Studies , Cytokines/metabolism , Disease Models, Animal , Eosinophils/drug effects , Eosinophils/metabolism , Eosinophils/virology , Host-Pathogen Interactions , Humans , Lectins/antagonists & inhibitors , Lectins/genetics , Lectins/metabolism , Mast Cells/drug effects , Mast Cells/metabolism , Mast Cells/virology , Mice, Transgenic , Peptide Hydrolases/metabolism , Respiratory Syncytial Virus Infections/metabolism , Respiratory Syncytial Virus Infections/prevention & control , Respiratory Syncytial Virus Infections/virology , Toll-Like Receptors/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL