Activation of TLR4 by viral glycoproteins: A double-edged sword?

Frontiers in Microbiology, Год журнала: 2022, Номер 13

Опубликована: Сен. 29, 2022

Recognition of viral infection by pattern recognition receptors is paramount for a successful immune response to infection. However, an unbalanced proinflammatory can be detrimental the host. Recently, multiple studies have identified that SARS-CoV-2 spike protein activates Toll-like receptor 4 (TLR4), resulting in induction cytokine expression. Activation TLR4 glycoproteins has also been observed context other models, including respiratory syncytial virus (RSV), dengue (DENV) and Ebola (EBOV). mechanisms involved virus-TLR4 interactions remained unclear. Here, we review act as pathogen-associated molecular patterns induce via TLR4. We explore current understanding underlying how are recognized discuss contribution activation pathogenesis. identify contentious findings research gaps highlight importance glycoprotein-mediated potential therapeutic approaches.

Язык: Английский

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SARS-CoV-2 spike protein as a bacterial lipopolysaccharide delivery system in an overzealous inflammatory cascade

Journal of Molecular Cell Biology, Год журнала: 2022, Номер 14(9)

Опубликована: Сен. 1, 2022

ABSTRACT Accumulating evidence indicates a potential role for bacterial lipopolysaccharide (LPS) in the overactivation of immune response during SARS-CoV-2 infection. LPS is recognized by Toll-like receptor 4, mediating proinflammatory effects. We previously reported that directly interacts with spike (S) protein and enhances activities. Using native gel electrophoresis hydrogen–deuterium exchange mass spectrometry, we showed binds to multiple hydrophobic pockets spanning both S1 S2 subunits S protein. Molecular simulations validated microscale thermophoresis binding assay revealed pocket lower affinity compared S1, suggesting as an intermediate transfer. Congruently, nuclear factor-kappa B (NF-κB) activation monocytic THP-1 cells strongly boosted S2. NF-κB reporter mice followed bioimaging, boosting effect was observed S2, former potentially facilitated proteolysis. The Omicron variant LPS, but reduced vitro vivo. Taken together, data provide molecular mechanism which augments LPS-mediated hyperinflammation.

Язык: Английский

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From Co-Infections to Autoimmune Disease via Hyperactivated Innate Immunity: COVID-19 Autoimmune Coagulopathies, Autoimmune Myocarditis and Multisystem Inflammatory Syndrome in Children

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(3), С. 3001 - 3001

Опубликована: Фев. 3, 2023

Neutrophilia and the production of neutrophil extracellular traps (NETs) are two many measures increased inflammation in severe COVID-19 that also accompany its autoimmune complications, including coagulopathies, myocarditis multisystem inflammatory syndrome children (MIS-C). This paper integrates currently disparate innate hyperactivation relates these to SARS-CoV-2 activation immunity. Aggregated data include Toll-like receptors (TLRs), nucleotide-binding oligomerization domain (NOD) receptors, NOD leucine-rich repeat pyrin-domain-containing (NLRPs), retinoic acid-inducible gene I (RIG-I) melanoma-differentiation-associated 5 (MDA-5). mainly activates virus-associated TLR3, TLR7, TLR8, NLRP3, RIG-1 MDA-5. Severe COVID-19, however, is characterized by additional TLR1, TLR2, TLR4, TLR5, TLR6, NOD1 NOD2, which primarily responsive bacterial antigens. The patterns Kawasaki disease, or MIS-C, mimic those rather than alone suggesting autoimmunity follows combined SARS-CoV-2-bacterial infections. Viral known synergize produce required support disease pathology. Additional studies demonstrate anti-bacterial antibodies account for autoantigen targets complications.

Язык: Английский

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Cyclophilin–CD147 interaction enables SARS-CoV-2 infection of human monocytes and their activation via Toll-like receptors 7 and 8

Frontiers in Immunology, Год журнала: 2025, Номер 16

Опубликована: Фев. 3, 2025

Monocytes and macrophages, as important constituents of the innate immune system, are equipped with multiple Toll-like-receptors (TLRs) to recognize invading pathogens, such SARS-CoV-2, mount an antiviral response. Nevertheless, their uncontrolled activation can lead hyperinflammation seen in severe COVID-19. Surprisingly, we observed that recombinant SARS-CoV-2 Spike (S) Nucleocapsid (N) proteins triggered only a weak proinflammatory response human peripheral blood monocytes. By employing THP-1 Jurkat NF-κB::eGFP reporter cell lines expressing specific TLRs, various TLR ligands blocking antibodies, determined surface including TLR2/1, TLR2/6 TLR4 do not play major role sensing. However, monocytes potently activated by replication-competent correlates viral uptake is monocytes, but lymphocytes. We show monocyte involves two distinct steps. Firstly, infects process independent S protein prime receptor angiotensin-converting enzyme 2. Instead, alternative CD147, which highly expressed on recognizes its well-known interaction partners cyclophilins A B incorporated into virions. Secondly, upon via cyclophilin-CD147 interaction, be inhibited CD147 antibodies or competition cyclophilin B, RNA recognized TLR7/8 endosomes, leading upregulation tumor necrosis factor (TNF), interleukin (IL)-1β IL-6, comprising core hyperinflammatory signature. Taken together, our data reveal novel mechanism how sense suggest targeting axis might beneficial alleviate overt myeloid-driven inflammation infection.

Язык: Английский

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The Yin and Yang of TLR4 in COVID-19

Cytokine & Growth Factor Reviews, Год журнала: 2024, Номер unknown

Опубликована: Окт. 1, 2024

Язык: Английский

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Growth hormone-releasing hormone antagonist MIA-602 inhibits inflammation induced by SARS-CoV-2 spike protein and bacterial lipopolysaccharide synergism in macrophages and human peripheral blood mononuclear cells

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Авг. 15, 2023

COVID-19 is characterized by an excessive inflammatory response and macrophage hyperactivation, leading, in severe cases, to alveolar epithelial injury acute respiratory distress syndrome. Recent studies have reported that SARS-CoV-2 spike (S) protein interacts with bacterial lipopolysaccharide (LPS) boost responses vitro, macrophages peripheral blood mononuclear cells (PBMCs), vivo. The hypothalamic hormone growth hormone-releasing (GHRH), addition promoting pituitary GH release, exerts many functions, acting as a factor both malignant non-malignant cells. GHRH antagonists, turn, display potent antitumor effects antinflammatory activities different cell types, including lung endothelial However, date, the role of antagonists remains unexplored. Here, we examined ability antagonist MIA-602 reduce inflammation human THP-1-derived PBMCs stimulated S LPS combination. Western blot immunofluorescence analysis revealed presence receptor its splice variant SV1 THP-1 PBMCs. Exposure combination increased mRNA levels secretion TNF-α IL-1β, well IL-8 MCP-1 gene expression, effect hampered MIA-602. Similarly, hindered IL-1β reduced levels. Mechanistically, blunted LPS-induced activation pathways cells, such NF-κB, STAT3, MAPK ERK1/2 JNK. also attenuated oxidative stress PBMCs, decreasing ROS production, iNOS COX-2 levels, MMP9 activity. Finally, prevented synergism on NF-кB nuclear translocation Overall, these findings demonstrate novel for MIA class suggest their potential development treatment diseases, related comorbidities.

Язык: Английский

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The dangerous liaisons in innate immunity involving recombinant proteins and endotoxins: Examples from the literature and the Leptospira field

Journal of Biological Chemistry, Год журнала: 2023, Номер 300(1), С. 105506 - 105506

Опубликована: Ноя. 27, 2023

Язык: Английский

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The unique ORF8 protein from SARS-CoV-2 binds to human dendritic cells and induces a hyper-inflammatory cytokine storm

Journal of Molecular Cell Biology, Год журнала: 2023, Номер 15(10)

Опубликована: Окт. 1, 2023

Abstract The novel coronavirus pandemic, first reported in December 2019, was caused by the severe acute respiratory syndrome 2 (SARS-CoV-2). SARS-CoV-2 infection leads to a strong immune response and activation of antigen-presenting cells, which can elicit distress (ARDS) characterized rapid onset widespread inflammation, so-called cytokine storm. In viral infections, monocytes are recruited into lung subsequently differentiate dendritic cells (DCs). DCs critical players development inflammation that causes ARDS. Here, we focus on interaction specific open reading frame protein, ORF8, with DCs. We show ORF8 binds DCs, pre-maturation differentiating induces secretion multiple proinflammatory cytokines these cells. addition, identified DC-SIGN as possible partner Blockade reduced production IL-1β, IL-6, IL-12p70, TNF-α, MCP-1 (also named CCL2), IL-10 Therefore, neutralizing antibody blocking ORF8-mediated chemokine could be an improved therapeutic strategy against SARS-CoV-2.

Язык: Английский

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Mechanistic insights into SARS-CoV-2 spike protein induction of the chemokine CXCL10

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Май 16, 2024

During a SARS-CoV-2 infection, macrophages recognize viral components resulting in cytokine production. While this response fuels virus elimination, overexpression of cytokines can lead to severe COVID-19. Previous studies suggest that the spike protein (S) elicit production via transcription factor NF-κB and toll-like receptors (TLRs). In study, we found that: (i) S S2 subunit induce CXCL10, chemokine implicated COVID-19, gene expression by human macrophage cells (THP-1); (ii) glycogen synthase kinase-3 inhibitor attenuates induction; (iii) do not activate but IRF; (iv) require TLR2 CXCL10 or (v) peripheral blood mononuclear (PBMCs). We also discovered cellular response, lack thereof, is function recombinant used. such finding raises possibility confounding LPS contamination, offer evidence potential contaminating does underly induced increases CXCL10. Combined, these results provide insights into complex immune possible therapeutic targets for

Язык: Английский

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SARS-CoV-2 S1 protein induces IgG-mediated platelet activation and is prevented by 1.8-cineole

Biomedicine & Pharmacotherapy, Год журнала: 2025, Номер 187, С. 118100 - 118100

Опубликована: Апрель 29, 2025

Язык: Английский

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