Neutrophils cause critical illness in COVID-19 and reveal CDK6 inhibitors as potential treatment (original) (raw)
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2021
Despite the recent development of vaccines and monoclonal antibodies preventing SARS-CoV-2 infection, treating critically ill COVID-19 patients still remains a top goal. In principle, drug repurposing – the use of an already existing drug for a new indication – could provide a shortcut to a treatment. However, drug repurposing is often very speculative due to lack of clinical evidence. We report here on a methodology to find and test drug target candidates for drug repurposing. Using UK Biobank data, we matched critically ill COVID-19 cases with healthy controls and screened for significant differences in 33 blood cell types, 30 blood biochemistries, and body mass index. Significant differences in traits that have been associated with critically ill COVID-19 status in prior literature, such as alanine aminotransferase, body mass index, C-reactive protein, and neutrophil cell count, were further investigated. In-depth statistical analysis of COVID-19 associated traits and their genet...
2022
Despite the recent development of vaccines and monoclonal antibodies preventing SARS-CoV-2 infection, treating critically ill COVID-19 patients still remains a top goal. In principle, drug repurposing -- the use of an already existing drug for a new indication -- could provide a shortcut to a treatment. However, drug repurposing is often very speculative due to lack of clinical evidence. We report here on a methodology to find and test drug target candidates for drug repurposing. Using UK Biobank data, we screened for significant differences in 33 blood cell types, 30 blood biochemistries, and body mass index between an infectious disease phenotype and healthy controls. We then matched critically ill COVID-19 cases with controls that exhibited mild or no symptoms after SARS-CoV-2 infection. Using data from the UK Biobank, we describe a workflow to find evidence for high neutrophil cell count and high concentrations of blood triglycerides as predictors of the immune overreaction in c...
Science Advances
Despite the availability of highly efficacious vaccines, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lacks effective drug treatment, which results in a high rate of mortality. To address this therapeutic shortcoming, we applied a systems biology approach to the study of patients hospitalized with severe COVID. We show that, at the time of hospital admission, patients who were equivalent on the clinical ordinal scale displayed significant differential monocyte epigenetic and transcriptomic attributes between those who would survive and those who would succumb to COVID-19. We identified messenger RNA metabolism, RNA splicing, and interferon signaling pathways as key host responses overactivated by patients who would not survive. Those pathways are prime drug targets to reduce mortality of critically ill patients with COVID-19, leading us to identify tacrolimus, zotatifin, and nintedanib as three strong candidates for treat...
Journal of Personalized Medicine
The coronavirus disease 2019 (COVID-19) pandemic causes many morbidity and mortality cases. Despite several developed vaccines and antiviral therapies, some patients experience severe conditions that need intensive care units (ICU); therefore, precision medicine is necessary to predict and treat these patients using novel biomarkers and targeted drugs. In this study, we proposed a multi-level biological network analysis framework to identify key genes via protein–protein interaction (PPI) network analysis as well as survival analysis based on differentially expressed genes (DEGs) in leukocyte transcriptomic profiles, discover novel biomarkers using microRNAs (miRNA) from regulatory network analysis, and provide candidate drugs targeting the key genes using drug–gene interaction network and structural analysis. The results show that upregulated DEGs were mainly enriched in cell division, cell cycle, and innate immune signaling pathways. Downregulated DEGs were primarily concentrated ...
Disease severity-specific neutrophil signatures in blood transcriptomes stratify COVID-19 patients
Genome Medicine
Background The SARS-CoV-2 pandemic is currently leading to increasing numbers of COVID-19 patients all over the world. Clinical presentations range from asymptomatic, mild respiratory tract infection, to severe cases with acute respiratory distress syndrome, respiratory failure, and death. Reports on a dysregulated immune system in the severe cases call for a better characterization and understanding of the changes in the immune system. Methods In order to dissect COVID-19-driven immune host responses, we performed RNA-seq of whole blood cell transcriptomes and granulocyte preparations from mild and severe COVID-19 patients and analyzed the data using a combination of conventional and data-driven co-expression analysis. Additionally, publicly available data was used to show the distinction from COVID-19 to other diseases. Reverse drug target prediction was used to identify known or novel drug candidates based on finding from data-driven findings. Results Here, we profiled whole bloo...
2021
ABSTRACTDespite the availability of highly efficacious vaccines, Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) lacks effective drug treatment which results in a high rate of mortality. To address this therapeutic shortcoming, we applied a system biology approach to the study of patients hospitalized with severe COVID. We show that, at the time of hospital admission, patients who were equivalent on the clinical ordinal scale displayed significant differential monocyte epigenetic and transcriptomic attributes between those who would survive and those who would succumb to COVID-19. We identified mRNA metabolism, RNA splicing, and interferon signaling pathways as key host responses overactivated by patients who would not survive. Those pathways are prime drug targets to reduce mortality of critically ill COVID-19 patients leading us to identify Tacrolimus, Zotatifin, and Nintedanib as three strong candidates for treatm...
Integrative genomic analyses identify susceptibility genes underlying COVID-19 hospitalization
Nature Communications, 2021
Despite rapid progress in characterizing the role of host genetics in SARS-Cov-2 infection, there is limited understanding of genes and pathways that contribute to COVID-19. Here, we integrate a genome-wide association study of COVID-19 hospitalization (7,885 cases and 961,804 controls from COVID-19 Host Genetics Initiative) with mRNA expression, splicing, and protein levels (n = 18,502). We identify 27 genes related to inflammation and coagulation pathways whose genetically predicted expression was associated with COVID-19 hospitalization. We functionally characterize the 27 genes using phenome- and laboratory-wide association scans in Vanderbilt Biobank (n = 85,460) and identified coagulation-related clinical symptoms, immunologic, and blood-cell-related biomarkers. We replicate these findings across trans-ethnic studies and observed consistent effects in individuals of diverse ancestral backgrounds in Vanderbilt Biobank, pan-UK Biobank, and Biobank Japan. Our study highlights and...
Pharmacogenomics to Drive COVID-19 Therapy for Best Outcome in a Low Resource Setting
2020
Corona virus disease 2019 (COVID-19) has taken the world by storm with global infectivity and mortality of 3.5%. Since there is no specific treatment for COVID-19, several drugs have been repurposed to combat infection, these include drugs like anti-malarial – chloroquine, hydroxychloroquine, anti- diarrheal– loperamide and antipsychotic-promazine, which have been considered to be effective inhibitors as of viral binding to ACE2 receptor. The administration of these drugs is currently random and is the key factors responsible for varied treatment response, hence genes involved in drug metabolism should be analysed before planning therapy. Genes involved in metabolism of the listed drugs are ABCB1, CYP1A2, CYP2C8, CYP2C19, CYP3A4 and CYP2D6. Unpublished pharmacogenomic data from our internal cohort (75 cases) was analyzed to predict likely-responders and non-responders to propose drugs for COVID-19 drug therapy in our population. Preliminary data from random individuals without bias ...
Gene influencing in COVID-19 infection, disease severity and its Pharmacotherapy
2020
Current pandemic COVID-19 has severely affected the world, having a mortality rate ranging from 1 to 10% which is different for many countries. The time interval from symptoms to clinical recovery is 6-8 weeks and to death is 2 to 8 weeks. The increase in severity and fatality in COVID 19 is primarily due to the presence of comorbidities like cardiovascular disease, pre-existing lungs disease, hypertension, diabetes, obesity and cancer. As we already know that humans show the difference in drug responses because of their varied genetic make-up. Therefore, Population genomics gives an insight into the genetic characteristic of a population and it is critical in determining susceptibility, severity and natural protection against infectious diseases. Hence, this study was done to evaluate the population genetic makeup which is necessary to identify those who are at risk or protection from disease and develop genomics information, that would be useful in providing insight about COVID-19 disease severity or outcomes. Some of the proposed genetic gateways in COVID 19 pathogenesis are mentioned in this review that includes roles of ACE2 gene, HLA gene, Chromosome 3P21.31, ABO locus, genes responsible for cytokine storm, TLR-pathway, Family Mediterranean fever and G6PD deficiency. This review also emphasises the current treatment available in COVID-19 like hydroxychloroquine, azithromycin, RNA polymerase inhibitors, interleukin inhibitors, antivirals, ivermectin, doxycycline and their pharmacogenomics viewpoint. Such Pharmacogenomic studies are very helpful for physicians to choose and give accurate firstline therapy for COVID 19 patients.
Genetic mechanisms of critical illness in Covid-19
The subset of patients who develop critical illness in Covid-19 have extensive inflammation affecting the lungs1 and are strikingly different from other patients: immunosuppressive therapy benefits critically-ill patients, but may harm some non-critical cases.2 Since susceptibility to life-threatening infections and immune-mediated diseases are both strongly heritable traits, we reasoned that host genetic variation may identify mechanistic targets for therapeutic development in Covid-19.3GenOMICC (Genetics Of Mortality In Critical Care, genomicc.org) is a global collaborative study to understand the genetic basis of critical illness. Here we report the results of a genome-wide association study (GWAS) in 2244 critically-ill Covid-19 patients from 208 UK intensive care units (ICUs), representing >95% of all ICU beds. Ancestry-matched controls were drawn from the UK Biobank population study and results were confirmed in GWAS comparisons with two other population control groups: the...