757 publications from this institution
No abstract is provided for this article.
Dexamethasone, a corticosteroid, has been approved for use in the treatment of severe COVID-19, which is characterised by hyperinflammation and associated lung damage. However, dexamethasone shows no clinical benefit in the treatment of less severe disease, and prolonged treatment may lead to immunosuppression and an increased risk of opportunistic infections. Hence there is a need for more specific anti-inflammatory therapies which also prevent severe disease. The NLRP3 inflammasome is an intracellular signalling complex which is responsible for the cleavage and release of the cytokines IL-1β and IL-18 and has also been shown to be inhibited by dexamethasone. NLRP3 inflammasome activation is strongly correlated with COVID-19 severity and part of dexamethasone's clinical effect in COVID-19 may be via NLRP3 inhibition. Specific NLRP3 inhibitors are currently undergoing clinical trials for the treatment of COVID-19. In this review, we evaluate the evidence supporting the use of dexamethasone and speculate on the potential use of NLRP3 inhibitors to treat COVID-19 as a more specific approach that may not have the liabilities of dexamethasone.
A study of human B lymphocytes identifies an important synergy between NOD1 or NOD2 and TLRs in proliferation and activation.
No abstract is provided for this article.
Four families of PRRs (pattern-recognition receptors) have been identified as important components of innate immunity, participating in the sensory system for host defence against the invasion of infectious agents. The TLRs (Toll-like receptors) recognize a variety of conserved microbial PAMPs (pathogen-associated molecular patterns) derived from bacteria, viruses, protozoa and fungi. They work in synergy with the cytosolic NLRs [NOD (nucleotide binding and oligomerization domain)-like receptors] (which sense bacteria), RLRs [RIG-I (retinoic acid-inducible gene 1)-like receptors] (which sense viruses) and CLRs (C-type lectin receptors) (which sense fungi). All of these receptor families signal an increase in the expression of a range of immune and inflammatory genes. The structural architecture of these receptors is conserved, involving seven distinct domains: the LRR (leucine-rich repeat) domain, the TIR [Toll/IL (interleukin)-1 receptor] domain, the NBS (nucleotide-binding site), the CARD (caspase recruitment domain), the PYD (pyrin domain), the helicase domain and the CTLD (C-type lectin domain). Two other domains, the Ig domain and the ITAM (immunoreceptor tyrosine-based activation motif) domain also participate and are also found in antibodies and TCRs (T-cell receptors), key proteins in adaptive immunity. This total of nine domains can therefore be used to construct immune systems which are common to many, if not all, species, allowing us to speculate on the minimum requirement for a complex immune system in structural terms. These insights are important for our overall understanding of the regulation of immunity in health and disease.
Recent studies on intracellular metabolism in dendritic cells (DCs) and macrophages provide new insights on the functioning of these critical controllers of innate and adaptive immunity. Both cell types undergo profound metabolic reprogramming in response to environmental cues, such as hypoxia or nutrient alterations, but importantly also in response to danger signals and cytokines. Metabolites such as succinate and citrate have a direct impact on the functioning of macrophages. Immunogenicity and tolerogenicity of DCs is also determined by anabolic and catabolic processes, respectively. These findings provide new prospects for therapeutic manipulation in inflammatory diseases and cancer.
Signaling by the toll-like receptor (TLR) and interleukin-1 receptor superfamily requires the adapter protein myeloid differentiation primary response protein 88 (MyD88). The recent determination of the structure of the so-called Myddosome provides us with new insights into the structural basis for innate immune signaling. Other information on the biochemistry and genetics of MyD88 and other adapters, such as MyDD adapter-like and TRIF-related adapter molecule, allows us to describe in some detail the signaling process activated by TLRs and provides new insights into the role these important proteins play in innate immunity.
Significant advances in our understanding of innate immunity have been made following the identification of three families of pathogen sensors: Toll-like receptors (TLRs), NOD-like receptors (NLRs) and RIG-I-like receptors (RLRs). Members of the TLR family recognize bacteria, viruses, fungi and protozoa; NLRs with known functions detect bacteria, and RLRs are anti-viral. It is likely that interplay between these families ensures the efficient co-ordination of innate immune responses, through either synergistic or co-operative signalling. Important interactions occur between TLRs and certain NLRs for inducing the pro-inflammatory cytokine interleukin (IL)-1β. TLRs induce pro-IL-1β production and prime NLR-containing multi-protein complexes, termed ‘inflammasomes’, to respond to bacterial products and products of damaged cells. This results in caspase-1 activation and the subsequent processing of pro-IL-1β to its active form. In this article, we hypothesize that during the first phase of the host response to infection, an important interplay occurs between these families, providing a substantial combinatorial repertoire in innate immunity.
No abstract is provided for this article.
No abstract is provided for this article.
No abstract is provided for this article.
<b>Introduction:</b> Dysregulated immune responses are a key feature of severe coronavirus disease 2019 (COVID-19) pathophysiology. Despite common symptoms there is disparity in patients' recovery, driving research into targeted therapies. <b>Aim:</b> To characterize the biological mechanisms in COVID-19 recovery. <b>Methods:</b> Serum proteomics (Olink platform) was carried out on 350 patients within the placebo and otilimab arms of OSCAR Part 1 (Otilimab in Severe COVID-19-Related Disease; NCT04376684). Patients were stratified by clinical response or mortality at Day 28, baseline severity, age (70y) and comorbidity status. Differentially expressed proteins (DEPs) at baseline were characterized. <b>Results:</b> Each stratification revealed 300+ DEPs that were assessed for enrichment of biological pathways. The tumor necrosis factor receptor 2 non-canonical NF-κB pathway was enriched in all groups, as was a cluster of pathways associated with dysfunctional protein metabolism and post‑translational modification. The size of this latter cluster was highly variable between groups. A distinct cluster of pathways linked to programmed cell death was associated with the fatal and ≥70y groups, but not observed in the severity or response analyses. Unique to the ≥70y group was a cluster of fibroblast growth factor-related and phospholipase C signaling pathways, potentially indicative of enhanced immune cell activation. <b>Conclusion:</b> These analyses reinforce the need for personalized treatment of severe COVID-19 and build rationale for poor outcomes in specific patient groups including older age. <b>Funded by GSK:</b> medical writing support provided by Fishawack Indicia Ltd, funded by GSK.
