Background Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, there has been increasing urgency to identify pathophysiological characteristics leading to severe clinical course in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Human leukocyte antigen alleles (HLA) have been suggested as potential genetic host factors that affect individual immune response to SARS-CoV-2. We sought to evaluate this hypothesis by conducting a multicenter study using HLA sequencing. Methods We analyzed the association between COVID-19 severity and HLAs in 435 individuals from Germany ( n = 135), Spain ( n = 133), Switzerland ( n = 20) and the United States ( n = 147), who had been enrolled from March 2020 to August 2020. This study included patients older than 18 years, diagnosed with COVID-19 and representing the full spectrum of the disease. Finally, we tested our results by meta-analysing data from prior genome-wide association studies (GWAS). Findings We describe a potential association of HLA-C*04:01 with severe clinical course of COVID-19. Carriers of HLA-C*04:01 had twice the risk of intubation when infected with SARS-CoV-2 (risk ratio 1.5 [95% CI 1.1–2.1], odds ratio 3.5 [95% CI 1.9–6.6], adjusted p -value = 0.0074). These findings are based on data from four countries and corroborated by independent results from GWAS. Our findings are biologically plausible, as HLA-C*04:01 has fewer predicted bindings sites for relevant SARS-CoV-2 peptides compared to other HLA alleles. Interpretation HLA-C*04:01 carrier state is associated with severe clinical course in SARS-CoV-2. Our findings suggest that HLA class I alleles have a relevant role in immune defense against SARS-CoV-2. Funding Funded by Roche Sequencing Solutions, Inc.
Reducing the expression of the Indy (Acronym for ‘I'm Not Dead, Yet’) gene in lower organisms promotes longevity and leads to a phenotype that resembles various aspects of caloric restriction. In C. elegans, the available data on life span extension is controversial. Therefore, the aim of this study was to determine the role of the C. elegans INDY homolog CeNAC2 in life span regulation and to delineate possible molecular mechanisms. siRNA against Indy/CeNAC2 was used to reduce expression of Indy/CeNAC2. Mean life span was assessed in four independent experiments, as well as whole body fat content and AMPK activation. Moreover, the effect of Indy/CeNAC2 knockdown in C. elegans with inactivating variants of AMPK (TG38) was studied. Knockdown of Indy/CeNAC2 increased life span by 22 ± 3% compared to control siRNA treated C. elegans, together with a decrease in whole body fat content by ~50%. Indy/CeNAC2 reduction also increased the activation of the intracellular energy sensor AMPK/aak2. In worms without functional AMPK/aak2, life span was not extended when Indy/CeNAC2 was reduced. Inhibition of glycolysis with deoxyglucose, an intervention known to increase AMPK/aak2 activity and life span, did not promote longevity when Indy/CeNAC2 was knocked down. Together, these data indicate that reducing the expression of Indy/CeNAC2 increases life span in C. elegans, an effect mediated at least in part by AMPK/aak2.
Due to the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), deepening the host genetic contribution to severe COVID-19 may further improve our understanding about underlying disease mechanisms. Here, we describe an extended GWAS meta-analysis of 3,260 COVID-19 patients with respiratory failure and 12,483 population controls from Italy, Spain, Norway and Germany, as well as hypothesis-driven targeted analysis of the human leukocyte antigen (HLA) region and chromosome Y haplotypes. We include detailed stratified analyses based on age, sex and disease severity. In addition to already established risk loci, our data identify and replicate two genome-wide significant loci at 17q21.31 and 19q13.33 associated with severe COVID-19 with respiratory failure. These associations implicate a highly pleiotropic ~0.9-Mb 17q21.31 inversion polymorphism, which affects lung function and immune and blood cell counts, and the NAPSA gene, involved in lung surfactant protein production, in COVID-19 pathogenesis.
Forkhead box O 3 (FOXO3) is a transcription factor involved in cell metabolism, inflammation and longevity. Here, we investigated if metformin can activate FOXO3 in human immune cells and affects the subsequent level of reactive oxygen/nitrogen species (ROS/RNS) in immune cells. AMP-activated protein kinase (AMPK) and FOXO3 activation were investigated by immunoblot or flow cytometry (FC) analysis, respectively. FOXO3 target gene expression was quantified by real-time PCR. ROS/RNS measurement using dichlorodihydrofluorescein diacetate (DCFH-DA) dye was investigated by FC. The role of the FOXO3 single nucleotide polymorphisms (SNPs) rs12212067, rs2802292 and rs12206094 on ROS/RNS production was studied using allelic discrimination PCR. Metformin induced activation of AMPK (pT172) and FOXO3 (pS413). ROS/RNS level was reduced in immune cells after metformin stimulation accompanied by induction of the FOXO3 targets mitochondrial superoxide dismutase and cytochrome c. Studies in Foxo3 deficient (Foxo3-/-) mouse splenocytes confirmed that metformin mediates its effects via Foxo3 as it attenuates ROS/RNS in myeloid cells of wildtype (WT) but not of Foxo3-/- mice. Our results suggest that FOXO3 can be activated by metformin leading to reduced ROS/RNS level in immune cells. This may add to the beneficial clinical effects of metformin observed in large cohort studies on longevity, cardiovascular and cancer risk.
Adiponectin (APN) is a multifunctional adipocytokine that inhibits myocardial fibrosis, dilatation, and left ventricular (LV) dysfunction after myocardial infarction (MI). Coxsackievirus B3 (CVB3) myocarditis is associated with intense extracellular matrix (ECM) remodeling which might progress to dilated cardiomyopathy. Here, we investigated in experimental CVB3 myocarditis whether APN inhibits adverse ECM remodeling following cardiac injury by affecting matrix metalloproteinase (MMP) expression. Cardiac injury was induced by CVB3 infection in APN knockout (APN‐KO) and wild‐type (WT) mice. Expression and activity of MMPs was quantified by qRT‐PCR and zymography, respectively. Activation of protein kinases was assessed by immunoblot. In cardiac myocytes and fibroblasts APN up‐regulates MMP‐9 expression via activation of 5′ adenosine monophosphate‐activated protein kinase (AMPK) and extracellular signal‐regulated kinase (ERK)1/2 which function as master regulators of inflammation‐induced MMP‐9 expression. Correspondingly, APN further increased up‐regulation of MMP‐9 expression triggered by tumor necrosis factor (TNF)α, lipopolysaccharide (LPS) and R‐848 in cardiac fibroblasts. In vivo, compared to WT mice cardiac MMP‐9 activity and serum levels of carboxy‐terminal telopeptide of type I collagen (ICTP) were attenuated in APN‐KO mice in subacute (day 7 p.i.) CVB3 myocarditis. Moreover, on day 3 and day 7 post CVB3 infection splenic MMP‐9 expression was diminished in APN‐KO mice correlating with attenuated myocardial immune cell infiltration in subacute CVB3 myocarditis. These results indicate that APN attenuates adverse cardiac remodeling following cardiac injury by up‐regulating MMP‐9 expression in cardiac and immune cells. Thus, APN mediates intensified collagen cleavage that might explain inhibition of LV fibrosis and dysfunction.
BackgroundSince the beginning of the coronavirus disease 2019 (COVID-19) pandemic, there has been increasing demand to identify predictors of severe clinical course in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Human leukocyte antigen alleles (HLA) have been suggested as potential genetic host factors. We sought to evaluate this hypothesis by conducting an international multicenter study using HLA sequencing with subsequent independent validation.MethodsWe analyzed a total of 332 samples. First, we enrolled 233 patients in Germany, Spain, and Switzerland for HLA and whole exome sequencing. Furthermore, we validated our results in a public data set (United States, n=99). Patients older than 18 years presenting with COVID-19 were included, representing the full spectrum of the disease. HLA candidate alleles were identified in the derivation cohort (n=92) and tested in two independent validation cohorts (n=240).ResultsWe identified HLA-C* 04:01 as a novel genetic predictor for severe clinical course in COVID-19. Carriers of HLA-C* 04:01 had twice the risk of intubation when infected with SARS-CoV-2 (hazard ratio 2.1, adjusted p-value=0.0036). Importantly, these findings were successfully replicated in an independent data set. Furthermore, our findings are biologically plausible, as HLA-C* 04:01 has fewer predicted bindings sites with relevant SARS-CoV-2 peptides as compared to other HLA alleles. Exome sequencing confirmed findings from HLA analysis.ConclusionsHLA-C* 04:01 carriage is associated with a twofold increased risk of intubation in patients infected with SARS-CoV-2. Testing for HLA-C* 04:01 could have clinical implications to identify high-risk patients and individualize management.
Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended GWAS meta-analysis of a well-characterized cohort of 3255 COVID-19 patients with respiratory failure and 12 488 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen (HLA) region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a ~ 0.9-Mb inversion polymorphism that creates two highly differentiated haplotypes and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative including non-Caucasian individuals, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung.
Background Fibroblast/myofibroblast transdifferentiation following acute cardiac injury (MI) is a major mechanism of scar formation and adverse remodeling regulated by TGFβ/SMAD3 signaling. Myofibroblasts represent phenotypically modulated cells characterized by α-smooth muscle actin (α-SMA) and constitute the main source of extracellular matrix proteins such as collagen type I in the healing infarct wound. Moreover, the recruitment of a specific monocyte/macrophages subset (Ly6Chigh and Ly6Clow) control the healing process in the infarcted wound. The forkhead transcription factor FOXO3a has recently been shown to inhibit cardiac hypertrophy by different stressors and is involved in the immune response following injury. Purpose We hypothesized that FOXO3a, a key regulator of cell differentiation, cell cycle and size as well as the stress response, might inhibit matricellular remodeling following myocardial infarction by regulating transdifferentiation of fibroblasts into myofibroblasts. Moreover, we hypothesized that Foxo3a−/− mice favor the recruitment of monocytes of the type Ly6Clow leading to an anti-inflammatory profile and thus the remodeling after injury. Methods Acute myocardial infarction was induced in FOXO3−/− and WT mice (FVB background) by permanent LAD ligation. The myocardial infarction size was determined via ECHO. Myofibroblast trans-differentiation and fibrosis markers were analyzed by QT-PCR and protein analysis. The differentiation of macrophages studied via FACS. IP/IF and Western blotting were used to test for a direct interaction between FOXO3a and SMAD3 in vitro. Results FOXO3a−/− mice showed significantly higher survival rates compared to WT littermates. Myocardial inflammation (Mac-1, LFA, CD3, CD45), injury markers such as Troponin T were similar in both groups on day 4 post-MI. Myocardial expression of alpha smooth muscle actin (ASMA) and Collagen1A1 (Col1A1), as well as numbers of cardiac CD11b+/F4–80+/Ly6clow macrophages was significantly enhanced in FOXO3a−/− mice 15 days post infarction. Moreover, Foxo3a−/− mice showed larger fibrotic areas following MI. Mechanistically, immunoprecipitation showed direct interaction of FOXO3a with SMAD3a that was enhanced following activation of the transcription factor leading to diminished SMAD3 downstream gene expression. Conclusion Our results indicate that FOXO3a acts as a direct inhibitor of TGF-β regulated myofibroblast differentiation and matrix remodeling via FOXO3a-SMAD3 interaction following MI. Moreover, a Foxo3a deficiency might lead to the recruitment of monocytes type Ly6Clow leading to an anti-inflammatory profile in the infarct wound. Therefore, FOXO3a collectively regulates cardiac hypertrophy and fibrosis/scar formation following MI. Thus, targeting the FOXO3a-SMAD3 signaling axis might be of future therapeutic interest. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): German Resaerch Foundation
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