Stimulator of interferon genes (STING) is known be involved in control of DNA viruses but has an unexplored role in control of RNA viruses. During infection with DNA viruses STING is activated ...downstream of cGAMP synthase (cGAS) to induce type I interferon. Here we identify a STING-dependent, cGAS-independent pathway important for full interferon production and antiviral control of enveloped RNA viruses, including influenza A virus (IAV). Further, IAV interacts with STING through its conserved hemagglutinin fusion peptide (FP). Interestingly, FP antagonizes interferon production induced by membrane fusion or IAV but not by cGAMP or DNA. Similar to the enveloped RNA viruses, membrane fusion stimulates interferon production in a STING-dependent but cGAS-independent manner. Abolishment of this pathway led to reduced interferon production and impaired control of enveloped RNA viruses. Thus, enveloped RNA viruses stimulate a cGAS-independent STING pathway, which is targeted by IAV.
Historically, human NK cells have been identified as CD3(-)CD56(+)CD16(±) lymphocytes. More recently it has been established that CD57 expression defines functionally discrete sub-populations of NK ...cells. On T cells, CD57 expression has been regarded as a marker of terminal differentiation and (perhaps wrongly) of anergy and senescence. Similarly, CD57 expression seems to identify the final stages of peripheral NK cell maturation; its expression increases with age and is associated with chronic infections, particularly human cytomegalovirus infection. However, CD57(+) NK cells are highly cytotoxic and their presence seems to be beneficial in a number of non-communicable diseases. The purpose of this article is to review our current understanding of CD57 expression as a marker of NK cell function and disease prognosis, as well as to outline areas for further research.
Frontotemporal dementia (FTD) is amongst the most prevalent early onset dementias and even though it is clinically, pathologically and genetically heterogeneous, a crucial involvement of metabolic ...perturbations in FTD pathology is being recognized. However, changes in metabolism at the cellular level, implicated in FTD and in neurodegeneration in general, are still poorly understood. Here we generate induced human pluripotent stem cells (hiPSCs) from patients carrying mutations in CHMP2B (FTD3) and isogenic controls generated via CRISPR/Cas9 gene editing with subsequent neuronal and glial differentiation and characterization. FTD3 neurons show a dysregulation of glutamate-glutamine related metabolic pathways mapped by
C-labelling coupled to mass spectrometry. FTD3 astrocytes show increased uptake of glutamate whilst glutamate metabolism is largely maintained. Using quantitative proteomics and live-cell metabolic analyses, we elucidate molecular determinants and functional alterations of neuronal and glial energy metabolism in FTD3. Importantly, correction of the mutations rescues such pathological phenotypes. Notably, these findings implicate dysregulation of key enzymes crucial for glutamate-glutamine homeostasis in FTD3 pathogenesis which may underlie vulnerability to neurodegeneration. Neurons derived from human induced pluripotent stem cells (hiPSCs) of patients carrying mutations in CHMP2B (FTD3) display major metabolic alterations compared to CRISPR/Cas9 generated isogenic controls. Using quantitative proteomics,
C-labelling coupled to mass spectrometry metabolic mapping and seahorse analyses, molecular determinants and functional alterations of neuronal and astrocytic energy metabolism in FTD3 were characterized. Our findings implicate dysregulation of glutamate-glutamine homeostasis in FTD3 pathogenesis. In addition, FTD3 neurons recapitulate glucose hypometabolism observed in FTD patient brains. The impaired mitochondria function found here is concordant with disturbed TCA cycle activity and decreased glycolysis in FTD3 neurons. FTD3 neuronal glutamine hypermetabolism is associated with up-regulation of PAG expression and, possibly, ROS production. Distinct compartments of glutamate metabolism can be suggested for the FTD3 neurons. Endogenous glutamate generated from glutamine via PAG may enter the TCA cycle via AAT (left side of neuron) while exogenous glutamate taken up from the extracellular space may be incorporated into the TCA cycle via GDH (right side of the neuron) FTD3 astrocytic glutamate uptake is upregulated whilst glutamate metabolism is largely maintained. Finally, pharmacological reversal of glutamate hypometabolism manifesting from decreased GDH expression should be explored as a novel therapeutic intervention for treating FTD3.
Information on the economic importance of wild meat to rural people is mainly based on small case studies conducted in limited geographical areas with high hunting intensities, which impede ...generalization of results. Through a one-year quarterly income survey of 7978 households in 24 countries across Latin America, Asia, and Africa, we show that 39% of the sampled households, by extrapolation representing ~150 million households in the Global South, ‘harvest’ wild meat. On average, wild meat makes up 2% of households' income of which own consumption accounts for 89%. Reliance on wild meat is highest among the poorest households and inversely related to their reliance on domestic animal income. Seasonally, reliance on wild meat is inversely related to other incomes, suggesting a gap filling function. The fact that hunting is of low economic importance but widespread and mostly for subsistence suggests that wild meat is important in rural households' diets. Through an approximated yield-effort curve estimation, we show that hunting appears economically sustainable in 78% of the observed communities although in most cases this might represent post-depletion sustainability. Our results imply that the effectiveness of wildlife conservation efforts is likely to be enhanced if rural food security is simultaneously improved.
•We examine the role of wild meat in 7978 households in 24 countries in the Global South•Reliance is highest for the poor and inversely related to reliance on domestic animal income.•Wild meat may have a gap-filling function as reliance is inversely related to other incomes.•Hunting appears economically sustainable in 78% of 201 communities but likely post-depletion.•Wildlife conservation will likely benefit from improved rural household food security.
•Comparative empirical evidence on the role of wild foods in supporting livelihoods.•Data set includes 24 countries, 58 sites, 333 villages, and 7975 households.•77.3% of households harvested wild ...foods from forest or non-forest environments.•461 wild foods were reported, more than twice the number of cultivated foods.•Wild foods fill strategic niches in rural households’ multiple nutritional needs.
This paper empirically quantifies and analyses (i) the economic contribution of wild foods to rural households, (ii) the household socio-economic, demographic, and geographical correlates of wild food income, and (iii) how wild foods can be better incorporated into integrative food security policies. We used household income data from 7975 households in 24 developing countries across three continents collected by the Poverty Environment Network (PEN). We found 77% of households to be engaged in wild food collection from forest and non-forest environments even though the share of wild food income in total household income was on average only 4%. Poorer households and households experiencing shocks derived higher income shares from wild foods. State land is the main source of forest-derived wild food income while private lands are most important for non-forest wild food income. Considerable regional variation in determinants and the direction of significant relationships indicate there is no one-size-fits-all approach to integrating wild foods into food and forest policies. However, our results reveal potential to increase household food security by integrating wild foods into national food policies in more customized ways.
Here, we applied a multi-omics approach (i) to examine molecular pathways related to de- and remyelination in multiple sclerosis (MS) lesions; and (ii) to translate these findings to the CSF proteome ...in order to identify molecules that are differentially expressed among MS subtypes.
To relate differentially expressed genes in MS lesions to de- and remyelination, we compared transcriptome of MS lesions to transcriptome of cuprizone (CPZ)-induced de- and remyelination. Protein products of the overlapping orthologous genes were measured within the CSF by quantitative proteomics, parallel reaction monitoring (PRM). Differentially regulated proteins were correlated with molecular markers of inflammation by using MesoScale multiplex immunoassay. Expression kinetics of differentially regulated orthologous genes and proteins were examined in the CPZ model.
In the demyelinated and remyelinated corpus callosum, we detected 1239 differentially expressed genes; 91 orthologues were also differentially expressed in MS lesions. Pathway analysis of these orthologues suggested that the TYROBP (DAP12)-TREM2 pathway, TNF-receptor 1, CYBA and the proteasome subunit PSMB9 were related to de- and remyelination. We designed 129 peptides representing 51 orthologous proteins, measured them by PRM in 97 individual CSF, and compared their levels between relapsing (n = 40) and progressive MS (n = 57). Four proteins were differentially regulated among relapsing and progressive MS: tyrosine protein kinase receptor UFO (UFO), TIMP-1, apolipoprotein C-II (APOC2), and beta-2-microglobulin (B2M). The orthologous genes/proteins in the mouse brain peaked during acute remyelination. UFO, TIMP-1 and B2M levels correlated inversely with inflammation in the CSF (IL-6, MCP-1/CCL2, TARC/CCL17). APOC2 showed positive correlation with IL-2, IL-16 and eotaxin-3/CCL26.
Pathology-based multi-omics identified four CSF markers that were differentially expressed in MS subtypes. Upregulated TIMP-1, UFO and B2M orthologues in relapsing MS were associated with reduced inflammation and reflected reparatory processes, in contrast to the upregulated orthologue APOC2 in progressive MS that reflected changes in lipid metabolism associated with increased inflammation.
Negative regulation of immune pathways is essential to achieve resolution of immune responses and to avoid excess inflammation. DNA stimulates type I IFN expression through the DNA sensor cGAS, the ...second messenger cGAMP, and the adaptor molecule STING. Here, we report that STING degradation following activation of the pathway occurs through autophagy and is mediated by p62/SQSTM1, which is phosphorylated by TBK1 to direct ubiquitinated STING to autophagosomes. Degradation of STING was impaired in p62‐deficient cells, which responded with elevated IFN production to foreign DNA and DNA pathogens. In the absence of p62, STING failed to traffic to autophagy‐associated vesicles. Thus, DNA sensing induces the cGAS‐STING pathway to activate TBK1, which phosphorylates IRF3 to induce IFN expression, but also phosphorylates p62 to stimulate STING degradation and attenuation of the response.
Synopsis
Stimulation of the cGAS‐STING pathway by cytosolic DNA leads to STING ubiquitination and degradation. The downstream cGAS‐STING kinase TBK1 also phosphorylates the selective autophagy receptor p62, which in turn directs STING for degradation by autophagy.
Abrogation of autophagy severely impaired DNA‐stimulated STING degradation.
p62 is essential for DNA‐stimulated STING degradation.
Cells lacking p62 have elevated interferon responses to cytoplasmic DNA and DNA pathogens.
TBK1 phosphorylates p62, which promoted STING degradation and regulation of the pathway.
Stimulation of the cGAS‐STING innate immunity pathway by cytosolic DNA leads to TBK1‐mediated phosphorylation of the selective autophagy receptor p62, directing ubiquitinated STING to autophagosomes and degradation.
Understanding the molecular pathways driving the acute antiviral and inflammatory response to SARS‐CoV‐2 infection is critical for developing treatments for severe COVID‐19. Here, we find decreasing ...number of circulating plasmacytoid dendritic cells (pDCs) in COVID‐19 patients early after symptom onset, correlating with disease severity. pDC depletion is transient and coincides with decreased expression of antiviral type I IFNα and of systemic inflammatory cytokines CXCL10 and IL‐6. Using an in vitro stem cell‐based human pDC model, we further demonstrate that pDCs, while not supporting SARS‐CoV‐2 replication, directly sense the virus and in response produce multiple antiviral (interferons: IFNα and IFNλ1) and inflammatory (IL‐6, IL‐8, CXCL10) cytokines that protect epithelial cells from de novo SARS‐CoV‐2 infection. Via targeted deletion of virus‐recognition innate immune pathways, we identify TLR7‐MyD88 signaling as crucial for production of antiviral interferons (IFNs), whereas Toll‐like receptor (TLR)2 is responsible for the inflammatory IL‐6 response. We further show that SARS‐CoV‐2 engages the receptor neuropilin‐1 on pDCs to selectively mitigate the antiviral interferon response, but not the IL‐6 response, suggesting neuropilin‐1 as potential therapeutic target for stimulation of TLR7‐mediated antiviral protection.
Synopsis
Plasmacytoid dendritic cells (pDCs) sense SARS‐CoV‐2 via two distinct innate immune pathways. The endosomal TLR7 pathway is activated upon sensing of viral RNA and this leads to type I IFN production. The TLR2 pathway is triggered by sensing of the viral envelope protein, inducing IL‐6 production. Interestingly, SARS‐CoV‐2 is able to specifically antagonize the TLR7‐IFN pathway via a CD304‐mediated signaling cascade.
Sensing of SARS‐CoV‐2 RNA by pDCs triggers a signaling cascade involving TLR7‐MyD88‐IRAK4‐TRAF6 to induce CXCL10 and, via IRF7 phosphorylation and translocation, type I and III Interferons. In parallel, SARS‐CoV‐2 envelope (E) glycoprotein is sensed by the extracellular TLR2/6 heterodimer facilitating production of IL‐6.
The secreted type I and III IFNs initiate autocrine and paracrine signals that induce the expression of IFN stimulated genes (ISGs), thereby facilitating an antiviral response that protects local epithelial cells against SARS‐CoV‐2 infection.
SARS‐CoV‐2 can counteract the protective IFN effects by inducing CD304 signaling, potentially interfering with IRF7 nuclear translocation, thereby inhibiting type I IFNα production and thus reducing the antiviral response generated by pDCs.
Sensing of SARS‐CoV‐2 by plasmacytoid dendritic cells (pDC) contributes to the anti‐viral and immunopathological responses.
Cardiac resynchronization therapy (CRT) is one of the most effective therapies for heart failure with reduced ejection fraction and leads to improved quality of life, reductions in heart failure ...hospitalization rates and all-cause mortality. Nevertheless, up to two-thirds of eligible patients are not referred for CRT. Furthermore, post-implantation follow-up is often fragmented and suboptimal, hampering the potential maximal treatment effect. This joint position statement from three European Society of Cardiology Associations, Heart Failure Association (HFA), European Heart Rhythm Association (EHRA) and European Association of Cardiovascular Imaging (EACVI), focuses on optimized implementation of CRT. We offer theoretical and practical strategies to achieve more comprehensive CRT referral and post-procedural care by focusing on four actionable domains: (i) overcoming CRT under-utilization, (ii) better understanding of pre-implant characteristics, (iii) abandoning the term 'non-response' and replacing this by the concept of disease modification, and (iv) implementing a dedicated post-implant CRT care pathway.
Studies to develop cell-based therapies for cancer and other diseases have consistently shown that purified human natural killer (NK) cells secrete cytokines and kill target cells after in vitro ...culture with high concentrations of cytokines. However, these assays poorly reflect the conditions that are likely to prevail in vivo in the early stages of an infection and have been carried out in a wide variety of experimental systems, which has led to contradictions within the literature. We have conducted a detailed kinetic and dose-response analysis of human NK cell responses to low concentrations of IL-12, IL-15, IL-18, IL-21, and IFN-α, alone and in combination, and their potential to synergize with IL-2. We find that very low concentrations of both innate and adaptive common γ chain cytokines synergize with equally low concentrations of IL-18 to drive rapid and potent NK cell CD25 and IFN-γ expression; IL-18 and IL-2 reciprocally sustain CD25 and IL-18Rα expression in a positive feedback loop; and IL-18 synergizes with FcγRIII (CD16) signaling to augment antibody-dependent cellular cytotoxicity. These data indicate that NK cells can be rapidly activated by very low doses of innate cytokines and that the common γ chain cytokines have overlapping but distinct functions in combination with IL-18. Importantly, synergy between multiple signaling pathways leading to rapid NK cell activation at very low cytokine concentrations has been overlooked in prior studies focusing on single cytokines or simple combinations. Moreover, although the precise common γ chain cytokines available during primary and secondary infections may differ, their synergy with both IL-18 and antigen-antibody immune complexes underscores their contribution to NK cell activation during innate and adaptive responses. IL-18 signaling potentiates NK cell effector function during innate and adaptive immune responses by synergy with IL-2, IL-15, and IL-21 and immune complexes.
PDF
