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The type II transmembrane serine proteases TMPRSS2 and HAT activate influenza viruses and the SARS-coronavirus (TMPRSS2) in cell culture and may play an important role in viral spread and pathogenesis in the infected host. However, it is at present largely unclear to what extent these proteases are expressed in viral target cells in human tissues. Here, we show that both HAT and TMPRSS2 are coexpressed with 2,6-linked sialic acids, the major receptor determinant of human influenza viruses, throughout the human respiratory tract. Similarly, coexpression of ACE2, the SARS-coronavirus receptor, and TMPRSS2 was frequently found in the upper and lower aerodigestive tract, with the exception of the vocal folds, epiglottis and trachea. Finally, activation of influenza virus was conserved between human, avian and porcine TMPRSS2, suggesting that this protease might activate influenza virus in reservoir-, intermediate- and human hosts. In sum, our results show that TMPRSS2 and HAT are expressed by important influenza and SARS-coronavirus target cells and could thus support viral spread in the human host.

Autophagy is an important cellular degradation pathway with a central role in metabolism as well as basic quality control, two processes inextricably linked to ageing. A decrease in autophagy is associated with increasing age, yet it is unknown if this is causal in the ageing process, and whether autophagy restoration can counteract these ageing effects. Here we demonstrate that systemic autophagy inhibition induces the premature acquisition of age-associated phenotypes and pathologies in mammals. Remarkably, autophagy restoration provides a near complete recovery of morbidity and a significant extension of lifespan; however, at the molecular level this rescue appears incomplete. Importantly autophagy-restored mice still succumb earlier due to an increase in spontaneous tumour formation. Thus, our data suggest that chronic autophagy inhibition confers an irreversible increase in cancer risk and uncovers a biphasic role of autophagy in cancer development being both tumour suppressive and oncogenic, sequentially. Autophagy declines with age, yet it is unclear if restoration of autophagy extends lifespan. Here, the authors demonstrate in murine models that the inhibition of Atg5 induces ageing phenotypes and reduces lifespan, whilst autophagy restoration partially reverses these phenotypes with accelerated tumorigenesis.

Genome-wide association studies (GWAS) have identified over 40 loci that affect risk of coronary artery disease (CAD) and the causal mechanisms at the majority of loci are unknown. Recent studies have suggested that many causal GWAS variants influence disease through altered transcriptional regulation in disease-relevant cell types. We explored changes in transcriptional regulation during a key pathophysiological event in CAD, the environmental lipid-induced transformation of macrophages to lipid-laden foam cells. We used a combination of open chromatin mapping with formaldehyde-assisted isolation of regulatory elements (FAIRE-seq) and enhancer and transcription factor mapping using chromatin immuno-precipitation (ChIP-seq) in primary human macrophages before and after exposure to atherogenic oxidized low-density lipoprotein (oxLDL), with resultant foam cell formation. OxLDL-induced foam cell formation was associated with changes in a subset of open chromatin and active enhancer sites that strongly correlated with expression changes of nearby genes. OxLDL-regulated enhancers were enriched for several transcription factors including C/EBP-beta, which has no previously documented role in foam cell formation. OxLDL exposure up-regulated C/EBP-beta expression and increased genomic binding events, most prominently around genes involved in inflammatory response pathways. Variants at CAD-associated loci were significantly and specifically enriched in the subset of chromatin sites altered by oxLDL exposure, including rs72664324 in an oxLDL-induced enhancer at the PPAP2B locus. OxLDL increased C/EBP beta binding to this site and C/EBP beta binding and enhancer activity were stronger with the protective A allele of rs72664324. In addition, expression of the PPAP2B protein product LPP3 was present in foam cells in human atherosclerotic plaques and oxLDL exposure up-regulated LPP3 in macrophages resulting in increased degradation of pro-inflammatory mediators. Our results demonstrate a genetic mechanism contributing to CAD risk at the PPAP2B locus and highlight the value of studying epigenetic changes in disease processes involving pathogenic environmental stimuli.

Coeliac disease (CeD) is a gastrointestinal enteropathy triggered by the consumption of gluten in predisposed individuals. A recent study showed that individuals were at more than 10% risk of having CeD if a first-degree relative also had the disease. However, only around 50% of CeD genetic heritability is attributable to specific loci, with the majority of this heritable risk attributed to the HLA loci, while the remaining 50% of disease risk is currently unidentified. We investigated the butyrophilin family of immunomodulators as novel CeD risk loci. We sequenced the butyrophilin loci of 48 CeD and 46 control patients and carried out gene-based burden testing on the captured single-nucleotide polymorphisms (SNPs). We found a significantly increased BTN2A1 gene burden in CeD patients. To validate these results, the SNP data of 3094 CeD patients and 29,762 control participants from the UK Biobank database were subjected to single-variant analyses. Fourteen BTN2A1, ten BTN3A1, and thirteen BTN3A2 SNPs were significantly associated with CeD status. These results are interesting, as BTN2A1 and BTN3A2 have not been associated with CeD risk previously but are known to modulate the activation of Vγ9+ γδ T cells and NK cells. Twenty of the 37 SNPs above were associated with CeD status independent of the risk-associated HLA genotypes. All twenty of these SNPs, alongside a novel SNP not included in the above SNPs, were associated with CeD in HLA-DQ2.5-matched case-control groups. We reaffirm the association of the BTN3A2 locus with CeD risk and identify BTN2A1 and BTN3A1 as putative novel CeD risk loci.

ObjectivesTo investigate whether people with coeliac disease are at increased risk of cardiovascular disease, including ischaemic heart disease, myocardial infarction, and stroke.DesignProspective analysis of a large cohort study.SettingUK Biobank database.Participants469 095 adults, of which 2083 had coeliac disease, aged 40-69 years from England, Scotland, and Wales between 2006 and 2010 without cardiovascular disease at baseline.Main outcome measureA composite primary outcome was relative risk of cardiovascular disease, ischaemic heart disease, myocardial infarction, and stroke in people with coeliac disease compared with people who do not have coeliac disease, assessed using Cox proportional hazard models.Results40 687 incident cardiovascular disease events occurred over a median follow-up of 12.4 years (interquartile range 11.5-13.1), with 218 events among people with coeliac disease. Participants with coeliac disease were more likely to have a lower body mass index and systolic blood pressure, less likely to smoke, and more likely to have an ideal cardiovascular risk score than people who do not have coeliac disease. Despite this, participants with coeliac disease had an incidence rate of 9.0 cardiovascular disease cases per 1000 person years (95% confidence interval 7.9 to 10.3) compared with 7.4 per 1000 person years (7.3 to 7.4) in people with no coeliac disease. Coeliac disease was associated with an increased risk of cardiovascular disease (hazard ratio 1.27 (95% confidence interval 1.11 to 1.45)), which was not influenced by adjusting for lifestyle factors (1.27 (1.11 to 1.45)), but was strengthened by further adjusting for other cardiovascular risk factors (1.44 (1.26 to 1.65)). Similar associations were identified for ischaemic heart disease and myocardial infarction but fewer stroke events were reported and no evidence of an association between coeliac disease and risk of stroke.ConclusionsIndividuals with coeliac disease had a lower prevalence of traditional cardiovascular risk factors but had a higher risk of developing cardiovascular disease than did people with no coeliac disease. Cardiovascular risk scores used in clinical practice might therefore not adequately capture the excess risk of cardiovascular disease in people with coeliac disease, and clinicians should be aware of the need to optimise cardiovascular health in this population.

As body weights and body mass indices have increased over time, we questioned the validity of correlating heart weight with body weight and whether tables from previous decades remain relevant. We investigated this by collecting details of heart weight, body weight, height, gender and age from 384 autopsy cases with no obvious heart or lung disease. Heart weights, body weights and heights showed a normal distribution for both genders. Heart weight correlated slightly better with body surface area than body weight and we present new reference charts derived from these data. The correlation between heart weight and body weight has changed little, despite increases in body weight and body mass index. As life expectancy is increasing, we investigated the effect of age on heart weight and demonstrated a small increase in heart weight relative to body surface area for both genders, in contrast to a previous study.

Hepcidin regulates systemic iron homeostasis. Suppression of hepcidin expression occurs physiologically in iron deficiency and increased erythropoiesis but is pathologic in thalassemia and hemochromatosis. Here we show that epigenetic events govern hepcidin expression. Erythropoiesis and iron deficiency suppress hepcidin via erythroferrone-dependent and -independent mechanisms, respectively, in vivo, but both involve reversible loss of H3K9ac and H3K4me3 at the hepcidin locus. In vitro, pan-histone deacetylase inhibition elevates hepcidin expression, and in vivo maintains H3K9ac at hepcidin-associated chromatin and abrogates hepcidin suppression by erythropoietin, iron deficiency, thalassemia, and hemochromatosis. Histone deacetylase 3 and its cofactor NCOR1 regulate hepcidin; histone deacetylase 3 binds chromatin at the hepcidin locus, and histone deacetylase 3 knockdown counteracts hepcidin suppression induced either by erythroferrone or by inhibiting bone morphogenetic protein signaling. In iron deficient mice, the histone deacetylase 3 inhibitor RGFP966 increases hepcidin, and RNA sequencing confirms hepcidin is one of the genes most differentially regulated by this drug in vivo. We conclude that suppression of hepcidin expression involves epigenetic regulation by histone deacetylase 3. Hepcidin controls systemic iron levels by inhibiting intestinal iron absorption and iron recycling. Here, Pasricha et al. demonstrate that the hepcidin-chromatin locus displays HDAC3-mediated reversible epigenetic modifications during both erythropoiesis and iron deficiency.

Fetal growth restriction (FGR) affects 5–10% of pregnancies, and can have serious consequences for both mother and child. Prevention and treatment are limited because FGR pathogenesis is poorly understood. Genetic studies implicate KIR and HLA genes in FGR, however, linkage disequilibrium, genetic influence from both parents, and challenges with investigating human pregnancies make the risk alleles and their functional effects difficult to map. Here, we demonstrate that the interaction between the maternal KIR2DL1, expressed on uterine natural killer (NK) cells, and the paternally inherited HLA-C*0501, expressed on fetal trophoblast cells, leads to FGR in a humanized mouse model. We show that the KIR2DL1 and C*0501 interaction leads to pathogenic uterine arterial remodeling and modulation of uterine NK cell function. This initial effect cascades to altered transcriptional expression and intercellular communication at the maternal-fetal interface. These findings provide mechanistic insight into specific FGR risk alleles, and provide avenues of prevention and treatment. Natural Killer cells regulate foetal growth. Here the authors use a humanized transgenic mouse to demonstrate that specific HLA-C KIR2DL interactions promote changes in maternal and foetal cell transcriptomes, resulting in modifications to placental vasculature, intercellular communications and foetal growth restriction.

Iron is critical for life but toxic in excess because of iron-catalysed formation of pro-oxidants that cause tissue damage in a range of disorders. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) orchestrates cell-intrinsic protective antioxidant responses, while the peptide hormone hepcidin maintains systemic iron homoeostasis, but is pathophysiologically decreased in haemochromatosis and β-thalassaemia. Here, we show that Nrf2 is activated by iron-induced, mitochondria-derived pro-oxidants and drives bone morphogenetic protein 6 (Bmp6) expression in liver sinusoidal endothelial cells, which in turn increases hepcidin synthesis by neighbouring hepatocytes. In Nrf2 knockout mice, the Bmp6–hepcidin response to oral and parenteral iron is impaired, and iron accumulation and hepatic damage are increased. Pharmacological activation of Nrf2 stimulates the Bmp6–hepcidin axis, improving iron homoeostasis in haemochromatosis and counteracting the inhibition of Bmp6 by erythroferrone in β-thalassaemia. We propose that Nrf2 links cellular sensing of excess toxic iron to the control of systemic iron homoeostasis and antioxidant responses, and may be a therapeutic target for iron-associated disorders. Iron homoeostasis is tightly orchestrated to avoid toxic iron overload. Here Lim and colleagues show that iron excess activates Nrf2 via mitochondrial reactive oxygen species, enhancing the expression of Bmp6 in liver sinusoidal endothelial cells, which in turn promotes hepcidin expression by hepatocytes, decreasing systemic iron levels.

Physiological effects of cellular hypoxia are sensed by prolyl hydroxylase (PHD) enzymes which regulate HIFs. Genetic interventions on HIF/PHD pathways reveal multiple phenotypes that extend the known biology of hypoxia. Recent studies unexpectedly implicate HIF in aspects of multiple immune and inflammatory pathways. However such studies are often limited by systemic lethal effects and/or use tissue-specific recombination systems, which are inherently irreversible, un-physiologically restricted and difficult to time. To study these processes better we developed recombinant mice which express tetracycline-regulated shRNAs broadly targeting the main components of the HIF/PHD pathway, permitting timed bi-directional intervention. We have shown that stabilization of HIF levels in adult mice through PHD2 enzyme silencing by RNA interference, or inducible recombination of floxed alleles, results in multi-lineage leukocytosis and features of autoimmunity. This phenotype was rapidly normalized on re-establishment of the hypoxia-sensing machinery when shRNA expression was discontinued. In both situations these effects were mediated principally through the Hif2a isoform. Assessment of cells bearing regulatory T cell markers from these mice revealed defective function and pro-inflammatory effects in vivo. We believe our findings have shown a new role for the PHD2/Hif2a couple in the reversible regulation of T cell and immune activity.