Project description:Individuals infected with SARS-CoV-2 vary greatly in their symptomatology and disease progression, likely as a result of numerous genetic, biological and environmental factors and their complex interactions. Meanwhile, the potential roles of microRNAs (miRNAs) in SARS-CoV-2 infection have not been fully described. MiRNAs have emerged as key post-transcriptional regulators of gene expression, and their dysregulation can be indicative of aberrant immune function. In this study, we characterize the potential roles of mIRNAs in early COVID-19 disease progression. We studied a diverse cohort of 259 patients admitted to hospitals in Abu Dhabi, United Arab Emirates to understand the clinical and biological factors associated with ICU admission during COVID-19 treatment, integrating electronic health records (EHR), global miRNA and RNA expression, and genotyping data. Using EHR, we identified 26 factors correlated with ICU admission, including 8 blood phenotypes such as neutrophil-to-lymphocyte ratio, Interleukin-6, and C-reactive protein levels. Using genome-wide miRNA expression data for a subset of 96 individuals from Southeast Asia and the Middle East and North Africa, we identified 27 miRNAs significantly associated with ICU admission (p < 0.01), and 97 miRNAs associated with at least one of the 8 blood phenotypes. [cross-cor] Integrating expression data for 632 miRNAs and genotyping data for ~260,000 SNPs, we identified 168 significant cis-expression quantitative trait loci (cis-eQTLs), of which 59 were associated with either ICU admission or one of the 8 blood phentoypes. Overall, our findings characterize the miRNA architecture of blood phenotypes during the early stages of COVID-19 infection, identify miRNAs associated with ICU admission and therefore COVID-19 disease severity, and suggest a potential genetic control of miRNA expression during early COVID-19 disease progression.
Project description:Individuals infected with SARS-CoV-2 vary greatly in their symptomatology and disease progression, likely as a result of numerous genetic, biological and environmental factors and their complex interactions. Meanwhile, the potential roles of microRNAs (miRNAs) in SARS-CoV-2 infection have not been fully described. MiRNAs have emerged as key post-transcriptional regulators of gene expression, and their dysregulation can be indicative of aberrant immune function. In this study, we characterize the potential roles of mIRNAs in early COVID-19 disease progression. We studied a diverse cohort of 259 patients admitted to hospitals in Abu Dhabi, United Arab Emirates to understand the clinical and biological factors associated with ICU admission during COVID-19 treatment, integrating electronic health records (EHR), global miRNA and RNA expression, and genotyping data. Using EHR, we identified 26 factors correlated with ICU admission, including 8 blood phenotypes such as neutrophil-to-lymphocyte ratio, Interleukin-6, and C-reactive protein levels. Using genome-wide miRNA expression data for a subset of 96 individuals from Southeast Asia and the Middle East and North Africa, we identified 27 miRNAs significantly associated with ICU admission (p < 0.01), and 97 miRNAs associated with at least one of the 8 blood phenotypes. [cross-cor] Integrating expression data for 632 miRNAs and genotyping data for ~260,000 SNPs, we identified 168 significant cis-expression quantitative trait loci (cis-eQTLs), of which 59 were associated with either ICU admission or one of the 8 blood phentoypes. Overall, our findings characterize the miRNA architecture of blood phenotypes during the early stages of COVID-19 infection, identify miRNAs associated with ICU admission and therefore COVID-19 disease severity, and suggest a potential genetic control of miRNA expression during early COVID-19 disease progression.
Project description:Acute quadriplegic myopathy (AQM) or critical illness myopathy (CIM) is frequently observed in intensive care unit (ICU) patients. In order to elucidate duration-dependent effects of the ICU intervention on molecular and functional networks that control the muscle wasting and weakness in AQM, gene expression profile was analyzed at time points varying from 6 hours to 14 days in a unique experimental rat model mimicking ICU conditions, i.e., post-synaptically paralyzed, mechanically ventilated and extensively monitored animals.
Project description:Septic patients treated in the intensive care unit (ICU) often develop multiple organ failure including persistent skeletal muscle dysfunction which results in the patient’s protracted recovery process. We have demonstrated that muscle mitochondrial enzyme activities are impaired in septic ICU patients resulting in decreased cellular energy which will interfere with muscle function and metabolism. Here we use detailed phenotyping and genomics to elucidate mechanisms leading to these impairments. Methodology/Principle Findings Utilising biopsy material from seventeen patients and ten age-matched controls we demonstrate that neither mitochondrial in vivo protein synthesis nor expression of mitochondrial genes are compromised. Indeed, there was partial activation of the mitochondrial biogenesis pathway involving NRF2?/GABP and its target genes TFAM, TFB1M and TFB2M yet clearly this failed to maintain mitochondrial function. We therefore utilised transcript profiling and pathway analysis of ICU patient skeletal muscle to generate insight into the molecular defects driving loss of muscle function and metabolic homeostasis. Gene ontology analysis of Affymetrix analysis demonstrated substantial loss of muscle specific genes, a global oxidative stress response related to most probably cytokine signalling, altered insulin related signalling and a substantial overlap between patients and muscle wasting/inflammatory animal models. MicroRNA 21 processing appeared defective suggesting that post-transcriptional protein synthesis regulation is altered by disruption of tissue microRNA expression. Finally, we were able to demonstrate that the phenotype of skeletal muscle in ICU patients is not merely one of inactivity, it appears to be an actively remodelling tissue, influenced by several mediators, all of which may be open to manipulation with the aim to improve clinical outcome. Conclusions/Significance This first combined protein and transcriptome based analysis of human skeletal muscle obtained from septic patients demonstrated that losses of mitochondria and muscle mass are accompanied by sustained protein synthesis (anabolic process) while dysregulation of transcription programmes appears to fail to compensate for increased damage and proteolysis. Our analysis identified both validated and novel clinically tractable targets to manipulate these failing processes and pursuit of these could lead to new potential treatments. Keywords: Disease state analysis
Project description:Acute quadriplegic myopathy (AQM) or critical illness myopathy (CIM) is frequently observed in intensive care unit (ICU) patients. In order to elucidate duration-dependent effects of the ICU intervention on molecular and functional networks that control the muscle wasting and weakness in AQM, gene expression profile was analyzed at time points varying from 6 hours to 14 days in a unique experimental rat model mimicking ICU conditions, i.e., post-synaptically paralyzed, mechanically ventilated and extensively monitored animals. A total of five sham operated controls and 23 experimental female Sprague-Dawley rats were included in this study. The experimental rats were anaesthetized, treated with the neuromuscular blocker (NMBA), α-cobrotoxin, mechanically ventilated and monitored for durations varying from 6h to 4 days (n=13), from 5 to 9 days (n=4), and from 9 to 14 days (n=6). Muscle biopsies were obtained from gastrocnemius muscle (proximal part) immediately after euthanasia and were quickly frozen in liquid propane cooled by liquid nitrogen, and stored at -80°C.RNA was extracted.