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1.
EClinicalMedicine ; 40: 101099, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34490415

RESUMO

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.

2.
EBioMedicine ; 69: 103439, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34157486

RESUMO

BACKGROUND: COVID-19 has been associated with Interstitial Lung Disease features. The immune transcriptomic overlap between Idiopathic Pulmonary Fibrosis (IPF) and COVID-19 has not been investigated. METHODS: we analyzed blood transcript levels of 50 genes known to predict IPF mortality in three COVID-19 and two IPF cohorts. The Scoring Algorithm of Molecular Subphenotypes (SAMS) was applied to distinguish high versus low-risk profiles in all cohorts. SAMS cutoffs derived from the COVID-19 Discovery cohort were used to predict intensive care unit (ICU) status, need for mechanical ventilation, and in-hospital mortality in the COVID-19 Validation cohort. A COVID-19 Single-cell RNA-sequencing cohort was used to identify the cellular sources of the 50-gene risk profiles. The same COVID-19 SAMS cutoffs were used to predict mortality in the IPF cohorts. FINDINGS: 50-gene risk profiles discriminated severe from mild COVID-19 in the Discovery cohort (P = 0·015) and predicted ICU admission, need for mechanical ventilation, and in-hospital mortality (AUC: 0·77, 0·75, and 0·74, respectively, P < 0·001) in the COVID-19 Validation cohort. In COVID-19, 50-gene expressing cells with a high-risk profile included monocytes, dendritic cells, and neutrophils, while low-risk profile-expressing cells included CD4+, CD8+ T lymphocytes, IgG producing plasmablasts, B cells, NK, and gamma/delta T cells. Same COVID-19 SAMS cutoffs were also predictive of mortality in the University of Chicago (HR:5·26, 95%CI:1·81-15·27, P = 0·0013) and Imperial College of London (HR:4·31, 95%CI:1·81-10·23, P = 0·0016) IPF cohorts. INTERPRETATION: 50-gene risk profiles in peripheral blood predict COVID-19 and IPF outcomes. The cellular sources of these gene expression changes suggest common innate and adaptive immune responses in both diseases. FUNDING: This work was supported in part by National Institute for Health Research Clinician Scientist Fellowship NIHR: CS-2013-13-017 (TMM); Action for Pulmonary Fibrosis Mike Bray fellowship (PLM); The National Heart, Lung, and Blood Institute (NHLBI) through award K01-HL-130704 (AJ); The University of South Florida (USF) Academic Support Fund and the USF Foundation, Ubben Fibrosis Fund (JHM).


Assuntos
COVID-19/genética , Transcriptoma , Adulto , Idoso , Biomarcadores/sangue , COVID-19/sangue , COVID-19/mortalidade , Feminino , Mortalidade Hospitalar , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida
3.
Clin Epigenetics ; 13(1): 118, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34034806

RESUMO

BACKGROUND: There are no prior reports that compare differentially methylated regions of DNA in blood samples from COVID-19 patients to samples collected before the SARS-CoV-2 pandemic using a shared epigenotyping platform. We performed a genome-wide analysis of circulating blood DNA CpG methylation using the Infinium Human MethylationEPIC BeadChip on 124 blood samples from hospitalized COVID-19-positive and COVID-19-negative patients and compared these data with previously reported data from 39 healthy individuals collected before the pandemic. Prospective outcome measures such as COVID-19-GRAM risk-score and mortality were combined with methylation data. RESULTS: Global mean methylation levels did not differ between COVID-19 patients and healthy pre-pandemic controls. About 75% of acute illness-associated differentially methylated regions were located near gene promoter regions and were hypo-methylated in comparison with healthy pre-pandemic controls. Gene ontology analyses revealed terms associated with the immune response to viral infections and leukocyte activation; and disease ontology analyses revealed a predominance of autoimmune disorders. Among COVID-19-positive patients, worse outcomes were associated with a prevailing hyper-methylated status. Recursive feature elimination identified 77 differentially methylated positions predictive of COVID-19 severity measured by the GRAM-risk score. CONCLUSION: Our data contribute to the awareness that DNA methylation may influence the expression of genes that regulate COVID-19 progression and represent a targetable process in that setting.


Assuntos
COVID-19/sangue , COVID-19/mortalidade , Metilação de DNA/fisiologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , New York/epidemiologia , Estudos Prospectivos , SARS-CoV-2
4.
Am J Respir Cell Mol Biol ; 65(3): 259-271, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33909984

RESUMO

Patients with pulmonary emphysema often develop locomotor muscle dysfunction, which is independently associated with disability and higher mortality in that population. Muscle dysfunction entails reduced force generation capacity, which partially depends on fibers' oxidative potential, yet very little mechanistic research has focused on muscle respiration in pulmonary emphysema. Using a recently established animal model of pulmonary emphysema-driven skeletal muscle dysfunction, we found downregulation of SDHC (succinate dehydrogenase subunit C) in association with lower oxygen consumption and fatigue tolerance in locomotor muscles. Reduced SDH activity has been previously observed in muscles from patients with pulmonary emphysema, and we found that SDHC is required to support respiration in cultured muscle cells. Moreover, in vivo gain of SDH function in emphysema animals' muscles resulted in better oxygen consumption rate and fatigue tolerance. These changes correlated with a larger number of relatively more oxidative type 2-A and 2X fibers and a reduced amount of 2B fibers. Our data suggest that SDHC is a key regulator of respiration and fatigability in pulmonary emphysema-driven skeletal muscles, which could be impactful in developing strategies aimed at attenuating this comorbidity.


Assuntos
Fadiga/enzimologia , Proteínas de Membrana/metabolismo , Músculo Esquelético/enzimologia , Consumo de Oxigênio , Enfisema Pulmonar/enzimologia , Animais , Modelos Animais de Doenças , Fadiga/genética , Fadiga/patologia , Fadiga/fisiopatologia , Proteínas de Membrana/genética , Camundongos , Camundongos Transgênicos , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Enfisema Pulmonar/genética , Enfisema Pulmonar/patologia , Enfisema Pulmonar/fisiopatologia
5.
Am J Physiol Regul Integr Comp Physiol ; 320(3): R250-R257, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33434104

RESUMO

The COVID19 pandemic has caused more than a million of deaths worldwide, primarily due to complications from COVID19-associated acute respiratory distress syndrome (ARDS). Controversy surrounds the circulating cytokine/chemokine profile of COVID19-associated ARDS, with some groups suggesting that it is similar to patients without COVID19 ARDS and others observing substantial differences. Moreover, although a hyperinflammatory phenotype associates with higher mortality in non-COVID19 ARDS, there is little information on the inflammatory landscape's association with mortality in patients with COVID19 ARDS. Even though the circulating leukocytes' transcriptomic signature has been associated with distinct phenotypes and outcomes in critical illness including ARDS, it is unclear whether the mortality-associated inflammatory mediators from patients with COVID19 are transcriptionally regulated in the leukocyte compartment. Here, we conducted a prospective cohort study of 41 mechanically ventilated patients with COVID19 infection using highly calibrated methods to define the levels of plasma cytokines/chemokines and their gene expressions in circulating leukocytes. Plasma IL1RA and IL8 were found positively associated with mortality, whereas RANTES and EGF negatively associated with that outcome. However, the leukocyte gene expression of these proteins had no statistically significant correlation with mortality. These data suggest a unique inflammatory signature associated with severe COVID19.


Assuntos
COVID-19/metabolismo , COVID-19/patologia , Inflamação/metabolismo , Síndrome do Desconforto Respiratório/mortalidade , SARS-CoV-2 , Idoso , COVID-19/mortalidade , Estudos de Coortes , Citocinas/genética , Citocinas/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade
6.
Cell Syst ; 12(1): 23-40.e7, 2021 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-33096026

RESUMO

We performed RNA-seq and high-resolution mass spectrometry on 128 blood samples from COVID-19-positive and COVID-19-negative patients with diverse disease severities and outcomes. Quantified transcripts, proteins, metabolites, and lipids were associated with clinical outcomes in a curated relational database, uniquely enabling systems analysis and cross-ome correlations to molecules and patient prognoses. We mapped 219 molecular features with high significance to COVID-19 status and severity, many of which were involved in complement activation, dysregulated lipid transport, and neutrophil activation. We identified sets of covarying molecules, e.g., protein gelsolin and metabolite citrate or plasmalogens and apolipoproteins, offering pathophysiological insights and therapeutic suggestions. The observed dysregulation of platelet function, blood coagulation, acute phase response, and endotheliopathy further illuminated the unique COVID-19 phenotype. We present a web-based tool (covid-omics.app) enabling interactive exploration of our compendium and illustrate its utility through a machine learning approach for prediction of COVID-19 severity.


Assuntos
COVID-19/sangue , COVID-19/genética , Aprendizado de Máquina , Análise de Sequência de RNA/métodos , Índice de Gravidade de Doença , Idoso , Idoso de 80 Anos ou mais , COVID-19/terapia , Estudos de Coortes , Feminino , Gelsolina/sangue , Gelsolina/genética , Humanos , Mediadores da Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Análise de Componente Principal/métodos
7.
Front Physiol ; 11: 600290, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33192616

RESUMO

Patients with chronic pulmonary conditions such as chronic obstructive pulmonary disease (COPD) often develop skeletal muscle dysfunction, which is strongly and independently associated with poor outcomes including higher mortality. Some of these patients also develop chronic CO2 retention, or hypercapnia, which is also associated with worse prognosis. While muscle dysfunction in these settings involve reduction of muscle mass and disrupted fibers' metabolism leading to suboptimal muscle work, mechanistic research in the field has been limited by the lack of adequate animal models. Over the last years, we have established a rodent model of COPD-induced skeletal muscle dysfunction that allowed a disaggregated interrogation of the cellular and physiological effects driven by COPD from the ones unique to hypercapnia. We found that while COPD and hypercapnia synergistically contribute to muscle atrophy, they are antagonistic processes regarding fibers respiratory capacity. We propose that AMP-activated protein kinase (AMPK) is a crucial regulator of CO2 signaling in hypercapnic muscles, which leads to both net protein catabolism and improved mitochondrial respiration to support a transition into a substrate-rich, fuel-efficient metabolic mode that allows muscle cells cope with the CO2 toxicity.

8.
medRxiv ; 2020 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-32743614

RESUMO

We performed RNA-Seq and high-resolution mass spectrometry on 128 blood samples from COVID-19 positive and negative patients with diverse disease severities. Over 17,000 transcripts, proteins, metabolites, and lipids were quantified and associated with clinical outcomes in a curated relational database, uniquely enabling systems analysis and cross-ome correlations to molecules and patient prognoses. We mapped 219 molecular features with high significance to COVID-19 status and severity, many involved in complement activation, dysregulated lipid transport, and neutrophil activation. We identified sets of covarying molecules, e.g., protein gelsolin and metabolite citrate or plasmalogens and apolipoproteins, offering pathophysiological insights and therapeutic suggestions. The observed dysregulation of platelet function, blood coagulation, acute phase response, and endotheliopathy further illuminated the unique COVID-19 phenotype. We present a web-based tool (covid-omics.app) enabling interactive exploration of our compendium and illustrate its utility through a comparative analysis with published data and a machine learning approach for prediction of COVID-19 severity.

10.
medRxiv ; 2020 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-32511515

RESUMO

The COVID19 pandemic is likely to cause more than a million of deaths worldwide, primarily due to complications from COVID19-associated acute respiratory distress syndrome (ARDS). Controversy surrounds the circulating cytokine/chemokine profile of COVID19-associated ARDS, with some groups suggesting that it is similar to non-COVID19 ARDS patients and others observing substantial differences. Moreover, while a hyperinflammatory phenotype associates with higher mortality in non-COVID19 ARDS, there is little information on the inflammatory landscape's association with mortality in COVID19 ARDS patients. Even though the circulating leukocytes' transcriptomic signature has been associated with distinct phenotypes and outcomes in critical illness including ARDS, it is unclear whether the mortality-associated inflammatory mediators from COVID19 patients are transcriptionally regulated in the leukocyte compartment. Here, we conducted a prospective cohort study of 41 mechanically ventilated patients with COVID19 infection using highly calibrated methods to define the levels of plasma cytokines/chemokines and their gene expressions in circulating leukocytes. Plasma IL1RA and IL8 were found positively associated with mortality while RANTES and EGF negatively associated with that outcome. However, the leukocyte gene expression of these proteins had no statistically significant correlation with mortality. These data suggest a unique inflammatory signature associated with severe COVID19.

11.
Int J Mol Sci ; 21(3)2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32023946

RESUMO

Skeletal muscle dysfunction is a major comorbidity in chronic obstructive pulmonary disease (COPD) and other pulmonary conditions. Chronic CO2 retention, or hypercapnia, also occur in some of these patients. Both muscle dysfunction and hypercapnia associate with higher mortality in these populations. Over the last years, we have established a mechanistic link between hypercapnia and skeletal muscle dysfunction, which is regulated by AMPK and causes depressed anabolism via reduced ribosomal biogenesis and accelerated catabolism via proteasomal degradation. In this review, we discuss the main findings linking AMPK with hypercapnic pulmonary disease both in the lungs and skeletal muscles, and also outline potential avenues for future research in the area based on knowledge gaps and opportunities to expand mechanistic research with translational implications.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Hipercapnia/metabolismo , Músculo Esquelético/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Animais , Dióxido de Carbono/metabolismo , Comorbidade , Humanos , Atrofia Muscular/metabolismo , Ribossomos/metabolismo
12.
J Appl Physiol (1985) ; 128(1): 134-148, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31774358

RESUMO

Patients with chronic obstructive pulmonary disease (COPD) usually develop skeletal muscle dysfunction, which represents a major comorbidity in these patients and is strongly associated with mortality and other poor outcomes. Although clinical data indicates that accelerated protein degradation and metabolic disruption are common associations of muscle dysfunction in COPD, there is very limited data on the mechanisms regulating the process, in part, due to the lack of research performed on a validated animal model of pulmonary emphysema. This model deficiency complicates the translational value of data generated with highly reductionist settings. Here, we use an established transgenic animal model of COPD based on inducible IL-13-driven pulmonary emphysema (IL-13TG) to interrogate the mechanisms of skeletal muscle dysfunction. Skeletal muscles from these emphysematous mice develop most features present in COPD patients, including atrophy, decreased oxygen consumption, and reduced force-generation capacity. Analysis of muscle proteome indicates downregulation of succinate dehydrogenase C (SDH-C), which correlates with reduced enzymatic activity, also consistent with previous clinical observations. Ontology terms identified with human data, such as ATP binding/bioenergetics are also downregulated in this animal's skeletal muscles. Moreover, chronic exercise can partially restore muscle mass, metabolic and force-generation capacity, and SDH activity in COPD mice. We conclude that this animal model of COPD/emphysema is an adequate platform to further investigate mechanisms of muscle dysfunction in this setting and demonstrates multiple approaches that can be used to address specific mechanisms regulating this process.NEW & NOTEWORTHY Skeletal muscle dysfunction is a relevant comorbidity in patients with chronic obstructive pulmonary disease (COPD). Mechanistic research in the area has so far been accomplished with models based on specific exposures to otherwise healthy animals, and no investigation using an established and validated animal model of COPD has been accomplished. We present an animal model of COPD that was previously shown to recapitulate pulmonary functional and histologic features present in patients with COPD, and demonstrates most of the features present in patients with pulmonary emphysema-associated muscle dysfunction, which we proposed as an adequate tool to develop mechanistic research in the area.


Assuntos
Interleucina-13/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular/terapia , Condicionamento Físico Animal/métodos , Enfisema Pulmonar/metabolismo , Enfisema Pulmonar/terapia , Animais , Feminino , Interleucina-13/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/patologia , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Enfisema Pulmonar/etiologia , Enfisema Pulmonar/patologia , Testes de Função Respiratória
13.
Am J Respir Cell Mol Biol ; 62(1): 74-86, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31264907

RESUMO

High CO2 retention, or hypercapnia, is associated with worse outcomes in patients with chronic pulmonary diseases. Skeletal muscle wasting is also an independent predictor of poor outcomes in patients with acute and chronic pulmonary diseases. Although previous evidence indicates that high CO2 accelerates skeletal muscle catabolism via AMPK (AMP-activated protein kinase)-FoxO3a-MuRF1 (E3-ubiquitin ligase muscle RING finger protein 1), little is known about the role of high CO2 in regulating skeletal muscle anabolism. In the present study, we investigated the potential role of high CO2 in attenuating skeletal muscle protein synthesis. We found that locomotor muscles from patients with chronic CO2 retention demonstrated depressed ribosomal gene expression in comparison with locomotor muscles from non-CO2-retaining individuals, and analysis of the muscle proteome of normo- and hypercapnic mice indicates reduction of important components of ribosomal structure and function. Indeed, mice chronically kept under a high-CO2 environment show evidence of skeletal muscle downregulation of ribosomal biogenesis and decreased protein synthesis as measured by the incorporation of puromycin into skeletal muscle. Hypercapnia did not regulate the mTOR pathway, and rapamycin-induced deactivation of mTOR did not cause a decrease in ribosomal gene expression. Loss-of-function studies in cultured myotubes showed that AMPKα2 regulates CO2-mediated reductions in ribosomal gene expression and protein synthesis. Although previous evidence has implicated TIF1A (transcription initiation factor-1α) and KDM2A (lysine-specific demethylase 2A) in AMPK-driven regulation of ribosomal gene expression, we found that these mediators were not required in the high CO2-induced depressed protein anabolism. Our research supports future studies targeting ribosomal biogenesis and protein synthesis to alleviate the effects of high CO2 on skeletal muscle turnover.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Dióxido de Carbono/efeitos adversos , Regulação para Baixo/efeitos dos fármacos , Proteínas Musculares/metabolismo , Músculo Esquelético/efeitos dos fármacos , Biossíntese de Proteínas/efeitos dos fármacos , Ribossomos/efeitos dos fármacos , Adolescente , Animais , Proteínas F-Box/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Pneumopatias/etiologia , Pneumopatias/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Proteínas Nucleares/metabolismo , Ribossomos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
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