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1.
Eur J Med Res ; 26(1): 146, 2021 Dec 17.
Article in English | MEDLINE | ID: covidwho-1582003

ABSTRACT

BACKGROUND: At the end of 2019, the world witnessed the emergence and ravages of a viral infection induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Also known as the coronavirus disease 2019 (COVID-19), it has been identified as a public health emergency of international concern (PHEIC) by the World Health Organization (WHO) because of its severity. METHODS: The gene data of 51 samples were extracted from the GSE150316 and GSE147507 data set and then processed by means of the programming language R, through which the differentially expressed genes (DEGs) that meet the standards were screened. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed on the selected DEGs to understand the functions and approaches of DEGs. The online tool STRING was employed to construct a protein-protein interaction (PPI) network of DEGs and, in turn, to identify hub genes. RESULTS: A total of 52 intersection genes were obtained through DEG identification. Through the GO analysis, we realized that the biological processes (BPs) that have the deepest impact on the human body after SARS-CoV-2 infection are various immune responses. By using STRING to construct a PPI network, 10 hub genes were identified, including IFIH1, DDX58, ISG15, EGR1, OASL, SAMD9, SAMD9L, XAF1, IFITM1, and TNFSF10. CONCLUSION: The results of this study will hopefully provide guidance for future studies on the pathophysiological mechanism of SARS-CoV-2 infection.


Subject(s)
COVID-19/genetics , Computational Biology/methods , Gene Expression Regulation/genetics , Lung/pathology , Protein Interaction Maps/genetics , COVID-19/pathology , Databases, Genetic , Gene Expression Profiling , Gene Ontology , Humans , Immunity, Humoral/genetics , Immunity, Humoral/immunology , Lung/virology , Neutrophil Activation/genetics , Neutrophil Activation/immunology , Neutrophils/immunology , SARS-CoV-2 , Transcriptome/genetics
2.
Elife ; 102021 06 01.
Article in English | MEDLINE | ID: covidwho-1513078

ABSTRACT

A voucher is a permanently preserved specimen that is maintained in an accessible collection. In genomics, vouchers serve as the physical evidence for the taxonomic identification of genome assemblies. Unfortunately, the vast majority of vertebrate genomes stored in the GenBank database do not refer to voucher specimens. Here, we urge researchers generating new genome assemblies to deposit voucher specimens in accessible, permanent research collections, and to link these vouchers to publications, public databases, and repositories. We also encourage scientists to deposit voucher specimens in order to recognize the work of local field biologists and promote a diverse and inclusive knowledge base, and we recommend best practices for voucher deposition to prevent taxonomic errors and ensure reproducibility and legality in genetic studies.


Subject(s)
Biological Specimen Banks , Databases, Genetic , Genomics , Specimen Handling , Animals , Data Accuracy , Humans , Phylogeny , Reproducibility of Results
3.
Cell Rep ; 37(7): 110020, 2021 11 16.
Article in English | MEDLINE | ID: covidwho-1509641

ABSTRACT

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types.


Subject(s)
COVID-19/genetics , SARS-CoV-2/genetics , Chromosome Mapping/methods , Computational Biology/methods , Databases, Genetic , Gene Expression/genetics , Gene Expression Profiling/methods , Genetic Predisposition to Disease/genetics , Genetic Variation/genetics , Genome-Wide Association Study/methods , Humans , Organ Specificity/genetics , Polymorphism, Single Nucleotide/genetics , Quantitative Trait Loci/genetics , SARS-CoV-2/pathogenicity , Severity of Illness Index , Transcriptome/genetics
4.
J Comput Biol ; 28(11): 1130-1141, 2021 11.
Article in English | MEDLINE | ID: covidwho-1483350

ABSTRACT

This article presents a novel scalable character-based phylogeny algorithm for dense viral sequencing data called SPHERE (Scalable PHylogEny with REcurrent mutations). The algorithm is based on an evolutionary model where recurrent mutations are allowed, but backward mutations are prohibited. The algorithm creates rooted character-based phylogeny trees, wherein all leaves and internal nodes are labeled by observed taxa. We show that SPHERE phylogeny is more stable than Nextstrain's, and that it accurately infers known transmission links from the early pandemic. SPHERE is a fast algorithm that can process >200,000 sequences in <2 hours, which offers a compact phylogenetic visualization of Global Initiative on Sharing All Influenza Data (GISAID).


Subject(s)
Mutation , Phylogeny , SARS-CoV-2/genetics , Algorithms , COVID-19/transmission , COVID-19/virology , Databases, Genetic , Humans
5.
J Comput Biol ; 28(11): 1113-1129, 2021 11.
Article in English | MEDLINE | ID: covidwho-1483349

ABSTRACT

The availability of millions of SARS-CoV-2 (Severe Acute Respiratory Syndrome-Coronavirus-2) sequences in public databases such as GISAID (Global Initiative on Sharing All Influenza Data) and EMBL-EBI (European Molecular Biology Laboratory-European Bioinformatics Institute) (the United Kingdom) allows a detailed study of the evolution, genomic diversity, and dynamics of a virus such as never before. Here, we identify novel variants and subtypes of SARS-CoV-2 by clustering sequences in adapting methods originally designed for haplotyping intrahost viral populations. We asses our results using clustering entropy-the first time it has been used in this context. Our clustering approach reaches lower entropies compared with other methods, and we are able to boost this even further through gap filling and Monte Carlo-based entropy minimization. Moreover, our method clearly identifies the well-known Alpha variant in the U.K. and GISAID data sets, and is also able to detect the much less represented (<1% of the sequences) Beta (South Africa), Epsilon (California), and Gamma and Zeta (Brazil) variants in the GISAID data set. Finally, we show that each variant identified has high selective fitness, based on the growth rate of its cluster over time. This demonstrates that our clustering approach is a viable alternative for detecting even rare subtypes in very large data sets.


Subject(s)
Cluster Analysis , Computational Biology/methods , Brazil , Databases, Genetic , Entropy , Humans , Monte Carlo Method , South Africa , United Kingdom , United States
7.
Sci Rep ; 11(1): 19839, 2021 10 06.
Article in English | MEDLINE | ID: covidwho-1454816

ABSTRACT

Computational drug repositioning aims at ranking and selecting existing drugs for novel diseases or novel use in old diseases. In silico drug screening has the potential for speeding up considerably the shortlisting of promising candidates in response to outbreaks of diseases such as COVID-19 for which no satisfactory cure has yet been found. We describe DrugMerge as a methodology for preclinical computational drug repositioning based on merging multiple drug rankings obtained with an ensemble of disease active subnetworks. DrugMerge uses differential transcriptomic data on drugs and diseases in the context of a large gene co-expression network. Experiments with four benchmark diseases demonstrate that our method detects in first position drugs in clinical use for the specified disease, in all four cases. Application of DrugMerge to COVID-19 found rankings with many drugs currently in clinical trials for COVID-19 in top positions, thus showing that DrugMerge can mimic human expert judgment.


Subject(s)
Antineoplastic Agents/pharmacology , COVID-19/drug therapy , Drug Repositioning/methods , Neoplasms/drug therapy , Antiviral Agents , COVID-19/genetics , COVID-19/metabolism , COVID-19/virology , Computational Biology/methods , Databases, Genetic , Databases, Pharmaceutical , Gene Regulatory Networks , Humans , Neoplasms/genetics , Neoplasms/metabolism , Neoplasms/virology , SARS-CoV-2/isolation & purification
8.
Nat Med ; 27(9): 1518-1524, 2021 09.
Article in English | MEDLINE | ID: covidwho-1402106

ABSTRACT

The current coronavirus disease 2019 (COVID-19) pandemic is the first to apply whole-genome sequencing near to real time, with over 2 million severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) whole-genome sequences generated and shared through the GISAID platform. This genomic resource informed public health decision-making throughout the pandemic; it also allowed detection of mutations that might affect virulence, pathogenesis, host range or immune escape as well as the effectiveness of SARS-CoV-2 diagnostics and therapeutics. However, genotype-to-phenotype predictions cannot be performed at the rapid pace of genomic sequencing. To prepare for the next phase of the pandemic, a systematic approach is needed to link global genomic surveillance and timely assessment of the phenotypic characteristics of novel variants, which will support the development and updating of diagnostics, vaccines, therapeutics and nonpharmaceutical interventions. This Review summarizes the current knowledge on key viral mutations and variants and looks to the next phase of surveillance of the evolving pandemic.


Subject(s)
COVID-19/epidemiology , Epidemiological Monitoring , Genome, Viral/genetics , Molecular Epidemiology/methods , SARS-CoV-2/genetics , Base Sequence/genetics , Clinical Decision-Making , Databases, Genetic , Humans , Public Health , Whole Genome Sequencing
9.
Sci Rep ; 11(1): 17473, 2021 09 01.
Article in English | MEDLINE | ID: covidwho-1392888

ABSTRACT

As for all newly-emergent pathogens, SARS-CoV-2 presents with a relative paucity of clinical information and experimental models, a situation hampering both the development of new effective treatments and the prediction of future outbreaks. Here, we find that a simple virus-free model, based on publicly available transcriptional data from human cell lines, is surprisingly able to recapitulate several features of the clinically relevant infections. By segregating cell lines (n = 1305) from the CCLE project on the base of their sole angiotensin-converting enzyme 2 (ACE2) mRNA content, we found that overexpressing cells present with molecular features resembling those of at-risk patients, including senescence, impairment of antibody production, epigenetic regulation, DNA repair and apoptosis, neutralization of the interferon response, proneness to an overemphasized innate immune activity, hyperinflammation by IL-1, diabetes, hypercoagulation and hypogonadism. Likewise, several pathways were found to display a differential expression between sexes, with males being in the least advantageous position, thus suggesting that the model could reproduce even the sex-related disparities observed in the clinical outcome of patients with COVID-19. Overall, besides validating a new disease model, our data suggest that, in patients with severe COVID-19, a baseline ground could be already present and, as a consequence, the viral infection might simply exacerbate a variety of latent (or inherent) pre-existing conditions, representing therefore a tipping point at which they become clinically significant.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , Gene Expression Profiling/methods , Up-Regulation , COVID-19/immunology , Cell Line , Databases, Genetic , Female , Humans , Immunity, Innate , Male , Models, Biological , Models, Theoretical , Sex Characteristics
10.
Viruses ; 13(5)2021 04 28.
Article in English | MEDLINE | ID: covidwho-1389539

ABSTRACT

It has now been over a year since SARS-CoV-2 first emerged in China, in December 2019, and it has spread rapidly around the world. Some variants are currently considered of great concern. We aimed to analyze the numbers of SARS-CoV-2 genome sequences obtained in different countries worldwide until January 2021. On 28 January 2021, we downloaded the deposited genome sequence origin from the GISAID database, and from the "Our world in data" website we downloaded numbers of SARS-CoV-2-diagnosed cases, numbers of SARS-CoV-2-associated deaths, population size, life expectancy, gross domestic product (GDP) per capita, and human development index per country. Files were merged and data were analyzed using Microsoft Excel software. A total of 450,968 SARS-CoV-2 genomes originating from 135 countries on the 5 continents were available. When considering the 19 countries for which the number of genomes per 100 deaths was >100, six were in Europe, while eight were in Asia, three were in Oceania and two were in Africa. Six (30%) of these countries are beyond rank 75, regarding the human development index and four (20%) are beyond rank 80 regarding GDP per capita. Moreover, the comparisons of the number of genomes sequenced per 100 deaths to the human development index by country show that some Western European countries have released similar or lower numbers of genomes than many African or Asian countries with a lower human development index. Previous data highlight great discrepancies between the numbers of available SARS-CoV-2 genomes per 100 cases and deaths and the ranking of countries regarding wealth and development.


Subject(s)
COVID-19/virology , Genome, Viral , SARS-CoV-2/genetics , Africa/epidemiology , Asia/epidemiology , COVID-19/epidemiology , Databases, Genetic , Europe/epidemiology , Global Health , High-Throughput Nucleotide Sequencing , Humans , Pandemics
11.
PLoS One ; 16(1): e0245280, 2021.
Article in English | MEDLINE | ID: covidwho-1388897

ABSTRACT

rfaRm is an R package providing a client-side interface for the Rfam database of non-coding RNA and other structured RNA elements. The package facilitates the search of the Rfam database by keywords or sequences, as well as the retrieval of all available information about specific Rfam families, such as member sequences, multiple sequence alignments, secondary structures and covariance models. By providing such programmatic access to the Rfam database, rfaRm enables genomic workflows to incorporate information about non-coding RNA, whose potential cannot be fully exploited just through interactive access to the database. The features of rfaRm are demonstrated by using it to analyze the SARS-CoV-2 genome as an example case.


Subject(s)
RNA, Untranslated/genetics , Sequence Analysis, RNA/methods , Software , Databases, Genetic , Humans , RNA, Untranslated/chemistry , RNA, Viral/chemistry , RNA, Viral/genetics , SARS-CoV-2/genetics
12.
BMC Res Notes ; 14(1): 10, 2021 Jan 06.
Article in English | MEDLINE | ID: covidwho-1388820

ABSTRACT

OBJECTIVE: This study describes the occurrence of a silent mutation in the RNA binding domain of nucleocapsid phosphoprotein (N protein) coding gene from SARS-CoV-2 that may consequence to a missense mutation by onset of another single nucleotide mutation. RESULTS: In the DNA sequence isolated from severe acute respiratory syndrome (SARS-CoV-2) in Iran, a coding sequence for the RNA binding domain of N protein was detected. The comparison of Chinese and Iranian DNA sequences displayed that a thymine (T) was mutated to cytosine (C), so "TTG" from China was changed to "CTG" in Iran. Both DNA sequences from Iran and China have been encoded for leucine. In addition, the second T in "CTG" in the DNA or uracil (U) in "CUG" in the RNA sequences from Iran can be mutated to another C by a missense mutation resulting from thymine DNA glycosylase (TDG) of human and base excision repair mechanism to produce "CCG" encoding for proline, which consequently may increase the affinity of the RNA binding domain of N protein to viral RNA and improve the transcription rate, pathogenicity, evasion from human immunity system, spreading in the human body, and risk of human-to-human transmission rate of SARS-CoV-2.


Subject(s)
COVID-19/genetics , Coronavirus Nucleocapsid Proteins/genetics , RNA, Viral/genetics , RNA-Binding Motifs/genetics , SARS-CoV-2/genetics , China , Databases, Genetic , Humans , Iran , Mutation, Missense , Phosphoproteins/genetics , Sequence Analysis, DNA , Silent Mutation
13.
Nucleic Acids Res ; 49(D1): D916-D923, 2021 01 08.
Article in English | MEDLINE | ID: covidwho-1387963

ABSTRACT

The GENCODE project annotates human and mouse genes and transcripts supported by experimental data with high accuracy, providing a foundational resource that supports genome biology and clinical genomics. GENCODE annotation processes make use of primary data and bioinformatic tools and analysis generated both within the consortium and externally to support the creation of transcript structures and the determination of their function. Here, we present improvements to our annotation infrastructure, bioinformatics tools, and analysis, and the advances they support in the annotation of the human and mouse genomes including: the completion of first pass manual annotation for the mouse reference genome; targeted improvements to the annotation of genes associated with SARS-CoV-2 infection; collaborative projects to achieve convergence across reference annotation databases for the annotation of human and mouse protein-coding genes; and the first GENCODE manually supervised automated annotation of lncRNAs. Our annotation is accessible via Ensembl, the UCSC Genome Browser and https://www.gencodegenes.org.


Subject(s)
COVID-19/prevention & control , Computational Biology/methods , Databases, Genetic , Genomics/methods , Molecular Sequence Annotation/methods , SARS-CoV-2/genetics , Animals , COVID-19/epidemiology , COVID-19/virology , Epidemics , Humans , Internet , Mice , Pseudogenes/genetics , RNA, Long Noncoding/genetics , SARS-CoV-2/metabolism , SARS-CoV-2/physiology , Transcription, Genetic/genetics
14.
Molecules ; 25(12)2020 Jun 26.
Article in English | MEDLINE | ID: covidwho-1389454

ABSTRACT

Viruses can be spread from one person to another; therefore, they may cause disorders in many people, sometimes leading to epidemics and even pandemics. New, previously unstudied viruses and some specific mutant or recombinant variants of known viruses constantly appear. An example is a variant of coronaviruses (CoV) causing severe acute respiratory syndrome (SARS), named SARS-CoV-2. Some antiviral drugs, such as remdesivir as well as antiretroviral drugs including darunavir, lopinavir, and ritonavir are suggested to be effective in treating disorders caused by SARS-CoV-2. There are data on the utilization of antiretroviral drugs against SARS-CoV-2. Since there are many studies aimed at the identification of the molecular mechanisms of human immunodeficiency virus type 1 (HIV-1) infection and the development of novel therapeutic approaches against HIV-1, we used HIV-1 for our case study to identify possible molecular pathways shared by SARS-CoV-2 and HIV-1. We applied a text and data mining workflow and identified a list of 46 targets, which can be essential for the development of infections caused by SARS-CoV-2 and HIV-1. We show that SARS-CoV-2 and HIV-1 share some molecular pathways involved in inflammation, immune response, cell cycle regulation.


Subject(s)
Coronavirus Infections/epidemiology , Coronavirus Infections/metabolism , Data Mining/methods , HIV Infections/epidemiology , HIV Infections/metabolism , Host-Pathogen Interactions/immunology , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/metabolism , Anti-Inflammatory Agents/therapeutic use , Antigens, Differentiation/genetics , Antigens, Differentiation/immunology , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , COVID-19 , Complement System Proteins/genetics , Complement System Proteins/immunology , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Databases, Genetic , Gene Expression Regulation , HIV Infections/drug therapy , HIV Infections/immunology , HIV-1/drug effects , HIV-1/immunology , HIV-1/pathogenicity , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/genetics , Humans , Immunity, Innate/drug effects , Immunologic Factors/therapeutic use , Inflammation , Interferons/genetics , Interferons/immunology , Interleukins/genetics , Interleukins/immunology , Metabolic Networks and Pathways/drug effects , Metabolic Networks and Pathways/genetics , Metabolic Networks and Pathways/immunology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Repressor Proteins/genetics , Repressor Proteins/immunology , SARS-CoV-2 , Signal Transduction , Toll-Like Receptors/genetics , Toll-Like Receptors/immunology , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/immunology
15.
Int J Mol Sci ; 21(13)2020 Jul 07.
Article in English | MEDLINE | ID: covidwho-1389380

ABSTRACT

The SARS-CoV-2 virus is a recently-emerged zoonotic pathogen already well adapted to transmission and replication in humans. Although the mutation rate is limited, recently introduced mutations in SARS-CoV-2 have the potential to alter viral fitness. In addition to amino acid changes, mutations could affect RNA secondary structure critical to viral life cycle, or interfere with sequences targeted by host miRNAs. We have analysed subsets of genomes from SARS-CoV-2 isolates from around the globe and show that several mutations introduce changes in Watson-Crick pairing, with resultant changes in predicted secondary structure. Filtering to targets matching miRNAs expressed in SARS-CoV-2-permissive host cells, we identified ten separate target sequences in the SARS-CoV-2 genome; three of these targets have been lost through conserved mutations. A genomic site targeted by the highly abundant miR-197-5p, overexpressed in patients with cardiovascular disease, is lost by a conserved mutation. Our results are compatible with a model that SARS-CoV-2 replication within the human host is constrained by host miRNA defences. The impact of these and further mutations on secondary structures, miRNA targets or potential splice sites offers a new context in which to view future SARS-CoV-2 evolution, and a potential platform for engineering conditional attenuation to vaccine development, as well as providing a better understanding of viral tropism and pathogenesis.


Subject(s)
Betacoronavirus/genetics , Genome, Viral , MicroRNAs/metabolism , RNA, Viral/chemistry , 3' Untranslated Regions , Base Sequence , COVID-19 , Coronavirus Infections/pathology , Coronavirus Infections/virology , Databases, Genetic , Humans , MicroRNAs/chemistry , MicroRNAs/genetics , Mutation , Nucleic Acid Conformation , Pandemics , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , RNA Splice Sites , RNA Splicing , SARS-CoV-2 , Sequence Alignment , Viral Nonstructural Proteins/genetics , Viral Proteins/chemistry , Viral Proteins/genetics , Viral Proteins/metabolism
16.
Sci Rep ; 11(1): 17365, 2021 08 30.
Article in English | MEDLINE | ID: covidwho-1379334

ABSTRACT

The SARS-CoV-2 pandemic prompts evaluation of recombination in human coronavirus (hCoV) evolution. We undertook recombination analyses of 158,118 public seasonal hCoV, SARS-CoV-1, SARS-CoV-2 and MERS-CoV genome sequences using the RDP4 software. We found moderate evidence for 8 SARS-CoV-2 recombination events, two of which involved the spike gene, and low evidence for one SARS-CoV-1 recombination event. Within MERS-CoV, 229E, OC43, NL63 and HKU1 datasets, we noted 7, 1, 9, 14, and 1 high-confidence recombination events, respectively. There was propensity for recombination breakpoints in the non-ORF1 region of the genome containing structural genes, and recombination severely skewed the temporal structure of these data, especially for NL63 and OC43. Bayesian time-scaled analyses on recombinant-free data indicated the sampled diversity of seasonal CoVs emerged in the last 70 years, with 229E displaying continuous lineage replacements. These findings emphasize the importance of genomic based surveillance to detect recombination in SARS-CoV-2, particularly if recombination may lead to immune evasion.


Subject(s)
Middle East Respiratory Syndrome Coronavirus/genetics , Recombination, Genetic , SARS Virus/genetics , SARS-CoV-2/genetics , Bayes Theorem , Databases, Genetic , Genome, Viral , Humans , Immune Evasion , Middle East Respiratory Syndrome Coronavirus/classification , SARS Virus/classification , SARS-CoV-2/classification , Spike Glycoprotein, Coronavirus/genetics , Viral Nonstructural Proteins/genetics
17.
J Comput Biol ; 28(11): 1104-1112, 2021 11.
Article in English | MEDLINE | ID: covidwho-1376272

ABSTRACT

A biological pathway is an ordered set of interactions between intracellular molecules having collective activity that impacts cellular function, for example, by controlling metabolite synthesis or by regulating the expression of sets of genes. They play a key role in advanced studies of genomics. However, existing pathway analytics methods are inadequate to extract meaningful biological structure underneath the network of pathways. They also lack automation. Given these circumstances, we have come up with a novel graph theoretic method to analyze disease-related genes through weighted network of biological pathways. The method automatically extracts biological structures, such as clusters of pathways and their relevance, significance of each pathway and gene, and so forth hidden in the complex network. We have demonstrated the effectiveness of the proposed method on a set of genes associated with coronavirus disease 2019.


Subject(s)
Algorithms , COVID-19/genetics , COVID-19/metabolism , Computational Biology/methods , Metabolic Networks and Pathways/genetics , Databases, Genetic , Humans
18.
Cells ; 10(9)2021 08 29.
Article in English | MEDLINE | ID: covidwho-1374308

ABSTRACT

Intercellular communication mediated by cytokines is critical to the development of immune responses, particularly in the context of infectious and inflammatory diseases. By releasing these small molecular weight peptides, the source cells can influence numerous intracellular processes in the target cells, including the secretion of other cytokines downstream. However, there are no readily available bioinformatic resources that can model cytokine-cytokine interactions. In this effort, we built a communication map between major tissues and blood cells that reveals how cytokine-mediated intercellular networks form during homeostatic conditions. We collated the most prevalent cytokines from the literature and assigned the proteins and their corresponding receptors to source tissue and blood cell types based on enriched consensus RNA-Seq data from the Human Protein Atlas database. To assign more confidence to the interactions, we integrated the literature information on cell-cytokine interactions from two systems of immunology databases, immuneXpresso and ImmunoGlobe. From the collated information, we defined two metanetworks: a cell-cell communication network connected by cytokines; and a cytokine-cytokine interaction network depicting the potential ways in which cytokines can affect the activity of each other. Using expression data from disease states, we then applied this resource to reveal perturbations in cytokine-mediated intercellular signalling in inflammatory and infectious diseases (ulcerative colitis and COVID-19, respectively). For ulcerative colitis, with CytokineLink, we demonstrated a significant rewiring of cytokine-mediated intercellular communication between non-inflamed and inflamed colonic tissues. For COVID-19, we were able to identify cell types and cytokine interactions following SARS-CoV-2 infection, highlighting important cytokine interactions that might contribute to severe illness in a subgroup of patients. Such findings have the potential to inform the development of novel, cytokine-targeted therapeutic strategies. CytokineLink is freely available for the scientific community through the NDEx platform and the project github repository.


Subject(s)
COVID-19/immunology , Cytokines/metabolism , Immunity , Inflammatory Bowel Diseases/immunology , Cell Communication , Colitis, Ulcerative/immunology , Colitis, Ulcerative/pathology , Databases, Genetic , Humans , Inflammatory Bowel Diseases/pathology , Signal Transduction
19.
PLoS One ; 16(8): e0256141, 2021.
Article in English | MEDLINE | ID: covidwho-1362089

ABSTRACT

SARS-CoV-2 requires serine protease, transmembrane serine protease 2 (TMPRSS2), and cysteine proteases, cathepsins B, L (CTSB/L) for entry into host cells. These host proteases activate the spike protein and enable SARS-CoV-2 entry. We herein performed genomic-guided gene set enrichment analysis (GSEA) to identify upstream regulatory elements altering the expression of TMPRSS2 and CTSB/L. Further, medicinal compounds were identified based on their effects on gene expression signatures of the modulators of TMPRSS2 and CTSB/L genes. Using this strategy, estradiol and retinoic acid have been identified as putative SARS-CoV-2 alleviation agents. Next, we analyzed drug-gene and gene-gene interaction networks using 809 human targets of SARS-CoV-2 proteins. The network results indicate that estradiol interacts with 370 (45%) and retinoic acid interacts with 251 (31%) human proteins. Interestingly, a combination of estradiol and retinoic acid interacts with 461 (56%) of human proteins, indicating the therapeutic benefits of drug combination therapy. Finally, molecular docking analysis suggests that both the drugs bind to TMPRSS2 and CTSL with the nanomolar to low micromolar affinity. The results suggest that these drugs can simultaneously target both the entry pathways of SARS-CoV-2 and thus can be considered as a potential treatment option for COVID-19.


Subject(s)
Cathepsin B/genetics , Cathepsin L/genetics , Estradiol/pharmacology , Genomics/methods , SARS-CoV-2/physiology , Serine Endopeptidases/genetics , Tretinoin/pharmacology , Cathepsin B/chemistry , Cathepsin L/chemistry , Databases, Genetic , Gene Expression Regulation, Enzymologic/drug effects , Gene Regulatory Networks/drug effects , Host-Pathogen Interactions , Humans , Models, Molecular , Molecular Docking Simulation , Protein Conformation , Protein Interaction Maps/drug effects , SARS-CoV-2/drug effects , Serine Endopeptidases/chemistry , Viral Proteins/genetics , Viral Proteins/metabolism , Virus Internalization/drug effects
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