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The Science Gallery, Trinity College Dublin, recently held an exhibition called “INFECTIOUS: STAY AWAY” that used art to illustrate infection and immunity. Luke O'Neill talks to one of the artists, Gordana Novakovic, about her involvement in this project.

Toll-like receptor (TLR) signaling activates the transcription factor NF-κB and production of proinflammatory cytokines. O'Neill and colleagues show that TLR signaling induces the microRNA miR-21 to dampen PDCD4 expression, which leads to less NF-κB activity and more IL-10 production.

Researchers gathered at the Wellcome Trust Genome Campus in Hinxton, Cambridge, for the first Innate Immune Memory Conference dedicated to the adaptive characteristics of innate immunity, to further the understanding of this newly described immunological process that probably has a central role in host defense and inflammation.

Over the past decade, the field of metabolism has witnessed remarkable scientific discoveries that reshaped the understanding of metabolic physiology and disease. As we launch Nature Metabolism, we look at what the future holds for metabolic research.

The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.

Could the BCG vaccine be used to bridge the gap until a specific COVID-19 vaccine is developed? Luke O’Neill and Mihai Netea discuss the science behind this approach.

In this Review, Luke O'Neill and Andrew Bowie discuss the role of the five adaptor proteins that are involved in Toll-like receptor (TLR) signalling, and provide a detailed molecular description of the earliest phase of TLR signal transduction.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

Pancreatic islets in type 2 diabetes show characteristic deposition of the amyloid polypeptide IAPP. O'Neill and colleagues show that IAPP induces IL-1β production via the NLRP3 inflammasome, which leads to beta-cell destruction.

Toll-like receptor signaling must be carefully regulated to avoid excessive inflammation. O'Neill and colleagues identify a splice variant of the adaptor TRAM that negatively regulates MyD88-independent pathway activated by Toll-like receptor 4.

Inhibition of the tricarboxylic acid cycle enzyme fumarate hydratase leads to deregulation of cytokine production in macrophages, which has implications in human diseases such as systemic lupus erythematosus.

Infectious disease associated with excessive inflammation can result in coagulopathy. Here the authors show use of the clinically approved therapy dimethyl fumarate, as well as the pre-clinical tool compound 4- octyl itaconate, modulate tissue factor related coagulopathy via inhibition of the myeloid type I interferon pathway-tissue factor axis.

A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

Whole-genome sequencing data for 2,778 cancer samples from 2,658 unique donors across 38 cancer types is used to reconstruct the evolutionary history of cancer, revealing that driver mutations can precede diagnosis by several years to decades.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

The chirality, or handedness, of nanoparticles is shown to be a key factor in determining how well such particles engage with the immune system — a finding that might help to inform the design of vaccines and anticancer therapeutics.

O’Carroll and Peace et al. provide a mechanism for the induction of type I interferons by the immunomodulatory compound itaconate, which involves inhibition of succinate dehydrogenase and release of mitochondrial double-stranded RNA.

Viral infection of macrophages causes metabolic rewiring, increasing the level of cytosolic fumarate owing to increased argininosuccinate synthase 1 expression. Fumarate succinates mitochondrial antiviral-signalling protein, promoting its ability to drive type I interferon production and antiviral immunity.

Induction of the microRNA miR-182 by interleukin 2 in helper T lymphocytes targets the transcription factor Foxo1 and promotes clonal expansion. Targeting this process opens new possibilities for adjuvancy, immunosuppression and anti-inflammatory therapeutics.

The activation of dendritic cells by Toll-like receptors leads to a rapid enhancement in glycolysis. Glucose is metabolized to pyruvate and from there to citrate in the mitochondria, which leads ultimately to membrane biosynthesis in the endoplasmic reticulum and Golgi to support the activation of dendritic cells.

Innate IL-17-producing T cells—in particular, adipose γδ17 T cells—are enriched in molecular-clock genes, and the circadian expression of IL-17A and RORγt by these cells has a role in maintaining local homeostasis and regulating lipogenesis.

A strain of Escherichia coli that causes urinary tract infections seems to take hold in the body by interfering with signaling through Toll-like receptors (TLRs). The mechanism involves a secreted bacterial protein that is taken up by cells and clogs up the TLR signaling mechanism (pages 399–406).

Toll-like receptor signaling induces the production of proinflammatory cytokines and type I interferons. Inhibition of the kinase IRAK1 by the phosphatase SHP-1 provides reciprocal regulation of these pathways by dampening the former while enhancing the latter.

The high levels of tissue-damaging reactive oxygen species that arise during a stroke or heart attack have been shown to be generated through the accumulation of the metabolic intermediate succinate. See Letter p.431

Neutrophil activation has been shown to rely on the pentose phosphate pathway (PPP) for NADPH generation and reactive oxygen species production. In this study, the authors identify a mechanism of neutrophil activation that is independent of the PPP but relies on the glycolytic enzyme pyruvate kinase M2 instead.

Macrophages can recycle nutrients and metabolites from bacteria that they phagocytose. New work is showing how this process can differ between dead and viable bacteria and the effect this distinction has on regulating immune responses and the immunometabolism of the macrophage.

The past 15 years have seen a breakthrough in the field of innate immunity. In this Timeline article, the authors discuss the early events that led to the identification of Toll-like receptors as the prototype pattern-recognition receptors that link innate and adaptive immune responses.

Age-related macular degeneration is a blinding disease associated with accumulation of aggregates called drusen in the retina. Now, Matthew Campbell and colleagues show that drusen can activate the inflammasome and that this activation protects against disease progression.

A selective, small-molecule inhibitor of NLRP3 suppresses activation of the inflammasome in vitro and in vivo and attenuates inflammatory disease.

Caspase 11 activation involves transcriptional upregulation and proteolytic cleavage. Here the authors show that prostaglandin E₂ prevents caspase-11-mediated pyroptosis, blocking caspase-11 mRNA and protein upregulation in macrophages and in vivo, and that mice lacking caspase-11 are strongly protected from allergic airway inflammation.

TLRs have a role in innate immunity and TLR4 recognizes lipopolysaccharide on the cell wall of Gram-negative bacteria. Now, Doyle and colleagues show that a transmembrane protein TMED7, similar to aDrosophilahomologue, can negatively control TLR4 signalling, suggesting a conserved role in innate immunity.

This Review highlights the Toll-like receptors (TLRs) that hold the most promise for drug discovery research, discussing agents that are in the discovery phase or in clinical trials, as well as new aspects of TLR-mediated signalling that might offer further possibilities of therapeutic manipulation.

Circadian controls of immune responses by the molecular clock have been reported, but the underlying mechanisms are unclear. Here the authors show that the master circadian gene, Bmal1, is essential for modulating the homeostasis of myeloid cells to control pro-inflammatory IL-17⁺/IFN-γ⁺ T cells in autoimmunity.

Recent advances in our understanding of the signalling pathways activated in inflammation have revealed several potential therapeutic targets. O'Neill reviews these pathways and speculates on the likelihood of drugs being developed that will limit inflammation without a deleterious impact on host defence.

Efficient statistical emulation of melting land ice under various climate scenarios to 2100 indicates a contribution from melting land ice to sea level increase of at least 13 centimetres sea level equivalent.

Many patients with Crohn disease, an inflammatory bowel disorder, carry mutations in NOD2. The finding that NOD2 normally dampens Toll-like receptor 2–mediated inflammation may explain this association.

Members of the Toll-like receptor–interleukin 1 receptor superfamily signal inflammatory responses. However, a member of this family is now shown to modulate these responses by acting as a negative regulator.

A case–control study investigating the causes of recent cases of acute hepatitis of unknown aetiology in 32 children identifies an association between adeno-associated virus infection and host genetics in disease susceptibility.

HIV-1 infection of CD4⁺ T cells triggers the interaction of the mitochondrial proteins NLRX1 and FASTKD5 to promote oxidative phosphorylation, leading to increased viral replication. It has now been shown that this process can be blocked by metformin.