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1.
Viruses ; 14(2)2022 02 15.
Article in English | MEDLINE | ID: covidwho-1687058

ABSTRACT

In February 2020, the municipality of Vo', a small town near Padua (Italy) was quarantined due to the first coronavirus disease 19 (COVID-19)-related death detected in Italy. To investigate the viral prevalence and clinical features, the entire population was swab tested in two sequential surveys. Here we report the analysis of 87 viral genomes, which revealed that the unique ancestor haplotype introduced in Vo' belongs to lineage B, carrying the mutations G11083T and G26144T. The viral sequences allowed us to investigate the viral evolution while being transmitted within and across households and the effectiveness of the non-pharmaceutical interventions implemented in Vo'. We report, for the first time, evidence that novel viral haplotypes can naturally arise intra-host within an interval as short as two weeks, in approximately 30% of the infected individuals, regardless of symptom severity or immune system deficiencies. Moreover, both phylogenetic and minimum spanning network analyses converge on the hypothesis that the viral sequences evolved from a unique common ancestor haplotype that was carried by an index case. The lockdown extinguished both the viral spread and the emergence of new variants.


Subject(s)
Family Characteristics , Genome, Viral , Haplotypes , Host Microbial Interactions/genetics , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , COVID-19/epidemiology , COVID-19/transmission , COVID-19/virology , Communicable Disease Control/methods , Evolution, Molecular , Humans , Italy/epidemiology , Mutation , Phylogeny , SARS-CoV-2/classification
2.
Viruses ; 14(2)2022 01 30.
Article in English | MEDLINE | ID: covidwho-1667347

ABSTRACT

Currently, SARS-CoV-2 causing coronavirus disease 2019 (COVID-19) is responsible for one of the most deleterious pandemics of our time. The interaction between the ACE2 receptors at the surface of human cells and the viral Spike (S) protein triggers the infection, making the receptor-binding domain (RBD) of the SARS-CoV-2 S-protein a focal target for the neutralizing antibodies (Abs). Despite the recent progress in the development and deployment of vaccines, the emergence of novel variants of SARS-CoV-2 insensitive to Abs produced in response to the vaccine administration and/or monoclonal ones represent a potential danger. Here, we analyzed the diversity of neutralizing Ab epitopes and assessed the possible effects of single and multiple mutations in the RBD of SARS-CoV-2 S-protein on its binding affinity to various antibodies and the human ACE2 receptor using bioinformatics approaches. The RBD-Ab complexes with experimentally resolved structures were grouped into four clusters with distinct features at sequence and structure level. The performed computational analysis indicates that while single amino acid replacements in RBD may only cause partial impairment of the Abs binding, moreover, limited to specific epitopes, the variants of SARS-CoV-2 with multiple mutations, including some which were already detected in the population, may potentially result in a much broader antigenic escape. Further analysis of the existing RBD variants pointed to the trade-off between ACE2 binding and antigenic escape as a key limiting factor for the emergence of novel SAR-CoV-2 strains, as the naturally occurring mutations in RBD tend to reduce its binding affinity to Abs but not to ACE2. The results provide guidelines for further experimental studies aiming to identify high-risk RBD mutations that allow for an antigenic escape.


Subject(s)
Antibodies, Neutralizing/metabolism , Antibodies, Viral/metabolism , Binding Sites, Antibody/genetics , Computational Biology/methods , Mutation , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Epitopes/metabolism , Host Microbial Interactions/genetics , Humans , Protein Binding , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology
3.
PLoS One ; 17(1): e0262832, 2022.
Article in English | MEDLINE | ID: covidwho-1643286

ABSTRACT

Tumor progression locus 2 (Tpl2) is a serine/threonine kinase that regulates the expression of inflammatory mediators in response to Toll-like receptors (TLR) and cytokine receptors. Global ablation of Tpl2 leads to severe disease in response to influenza A virus (IAV) infection, characterized by respiratory distress, and studies in bone marrow chimeric mice implicated Tpl2 in non-hematopoietic cells. Lung epithelial cells are primary targets and replicative niches of influenza viruses; however, the specific regulation of antiviral responses by Tpl2 within lung epithelial cells has not been investigated. Herein, we show that Tpl2 is basally expressed in primary airway epithelial cells and that its expression increases in both type I and type II airway epithelial cells (AECI and AECII) in response to influenza infection. We used Nkx2.1-cre to drive Tpl2 deletion within pulmonary epithelial cells to delineate epithelial cell-specific functions of Tpl2 during influenza infection in mice. Although modest increases in morbidity and mortality were attributed to cre-dependent deletion in lung epithelial cells, no alterations in host cytokine production or lung pathology were observed. In vitro, Tpl2 inhibition within the type I airway epithelial cell line, LET1, as well as genetic ablation in primary airway epithelial cells did not alter cytokine production. Overall, these findings establish that Tpl2-dependent defects in cells other than AECs are primarily responsible for the morbidity and mortality seen in influenza-infected mice with global Tpl2 ablation.


Subject(s)
Alveolar Epithelial Cells/metabolism , Host Microbial Interactions/genetics , Influenza A virus , MAP Kinase Kinase Kinases/metabolism , Orthomyxoviridae Infections/blood , Orthomyxoviridae Infections/immunology , Proto-Oncogene Proteins/metabolism , Animals , Cytokines/metabolism , Disease Models, Animal , Dogs , Female , MAP Kinase Kinase Kinases/genetics , Madin Darby Canine Kidney Cells , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Orthomyxoviridae Infections/mortality , Orthomyxoviridae Infections/virology , Proto-Oncogene Proteins/genetics
4.
Biochem Biophys Res Commun ; 592: 18-23, 2022 02 12.
Article in English | MEDLINE | ID: covidwho-1611627

ABSTRACT

The emergence of new SARS-CoV-2 variants poses a threat to the human population where it is difficult to assess the severity of a particular variant of the virus. Spike protein and specifically its receptor binding domain (RBD) which makes direct interaction with the ACE2 receptor of the human has shown prominent amino acid substitutions in most of the Variants of Concern. Here, by using all-atom molecular dynamics simulations we compare the interaction of Wild-type RBD/ACE2 receptor complex with that of the latest Omicron variant of the virus. We observed a very interesting diversification of the charge, dynamics and energetics of the protein complex formed upon mutations. These results would help us in understanding the molecular basis of binding of the Omicron variant with that of SARS-CoV-2 Wild-type.


Subject(s)
Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , COVID-19/virology , SARS-CoV-2/chemistry , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Amino Acid Substitution , Host Microbial Interactions/genetics , Host Microbial Interactions/physiology , Humans , Molecular Dynamics Simulation , Pandemics , Protein Binding , Protein Interaction Domains and Motifs , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Static Electricity
5.
Biochem Biophys Res Commun ; 592: 51-53, 2022 02 12.
Article in English | MEDLINE | ID: covidwho-1611626

ABSTRACT

Omicron is a new variant of SARS-CoV-2, which is currently infecting people around the world. Spike glycoprotein, an important molecule in pathogenesis of infection has been modeled and the interaction of its Receptor Binding Domain with human ACE-receptor has been analysed by simulation studies. Structural analysis of Omicron spike glycoprotein shows the 30 mutations to be distributed over all domains of the trimeric protein, wherein the mutant residues are seen to be participating in higher number of intra-molecular interactions including two salt bridges emanating from mutant residues thereby stabilizing their conformation, as compared to wild type. Complex of Receptor Binding Domain (RBD) with human ACE-2 receptor shows seven mutations at interacting interface comprising of two ionic interactions, eight hydrogen bonds and seven Van der Waals interactions. The number and quality of these interactions along with other binding biophysical parameters suggests more potency of RBD domain to the receptor as compared to the wild type counterpart. Results of this study explains the high transmissibility of Omicron variant of SARS-CoV-2 that is currently observed across the world.


Subject(s)
Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/transmission , COVID-19/virology , SARS-CoV-2/chemistry , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2/genetics , Biophysical Phenomena , COVID-19/metabolism , Host Microbial Interactions/genetics , Host Microbial Interactions/physiology , Humans , Molecular Dynamics Simulation , Mutation , Pandemics , Protein Interaction Domains and Motifs/genetics , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Structural Homology, Protein
6.
PLoS Comput Biol ; 17(12): e1009664, 2021 12.
Article in English | MEDLINE | ID: covidwho-1571973

ABSTRACT

The evolution of circulating viruses is shaped by their need to evade antibody response, which mainly targets the viral spike. Because of the high density of spikes on the viral surface, not all antigenic sites are targeted equally by antibodies. We offer here a geometry-based approach to predict and rank the probability of surface residues of SARS spike (S protein) and influenza H1N1 spike (hemagglutinin) to acquire antibody-escaping mutations utilizing in-silico models of viral structure. We used coarse-grained MD simulations to estimate the on-rate (targeting) of an antibody model to surface residues of the spike protein. Analyzing publicly available sequences, we found that spike surface sequence diversity of the pre-pandemic seasonal influenza H1N1 and the sarbecovirus subgenus highly correlates with our model prediction of antibody targeting. In particular, we identified an antibody-targeting gradient, which matches a mutability gradient along the main axis of the spike. This identifies the role of viral surface geometry in shaping the evolution of circulating viruses. For the 2009 H1N1 and SARS-CoV-2 pandemics, a mutability gradient along the main axis of the spike was not observed. Our model further allowed us to identify key residues of the SARS-CoV-2 spike at which antibody escape mutations have now occurred. Therefore, it can inform of the likely functional role of observed mutations and predict at which residues antibody-escaping mutation might arise.


Subject(s)
Evolution, Molecular , Influenza A Virus, H1N1 Subtype/genetics , Influenza A Virus, H1N1 Subtype/immunology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Viral Envelope Proteins/genetics , Viral Envelope Proteins/immunology , Animals , Antibodies, Viral/biosynthesis , Antigens, Viral/chemistry , Antigens, Viral/genetics , COVID-19/epidemiology , COVID-19/immunology , COVID-19/virology , Computational Biology , Coronavirus Infections/immunology , Coronavirus Infections/virology , Epitopes, B-Lymphocyte/chemistry , Epitopes, B-Lymphocyte/genetics , Hemagglutinin Glycoproteins, Influenza Virus/chemistry , Hemagglutinin Glycoproteins, Influenza Virus/genetics , Hemagglutinin Glycoproteins, Influenza Virus/immunology , Host Microbial Interactions/genetics , Host Microbial Interactions/immunology , Humans , Immune Evasion/genetics , Influenza, Human/immunology , Influenza, Human/virology , Models, Immunological , Molecular Dynamics Simulation , Mutation , Pandemics , Spike Glycoprotein, Coronavirus/chemistry , Viral Envelope Proteins/chemistry
7.
Comput Biol Chem ; 96: 107613, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1549716

ABSTRACT

Coronavirus Disease 2019 (COVID-19) is an ongoing global health emergency that has caused tremendous stress and loss of life worldwide. The viral spike glycoprotein is a critical molecule mediating transmission of SARS-CoV-2 by interacting with human ACE2. However, through the course of the pandemics, there has not been a thorough analysis of the spike protein mutations, and on how these mutants influence the transmission of SARS-CoV-2. Besides, cases of SARS-CoV-2 infection among pets and wild animals have been reported, so the susceptibility of these animals requires great attention to investigate, as they may also link to the renewed question of a possible intermediate host for SARS-CoV-2 before it was transmitted to humans. With over 226,000 SARS-CoV-2 sequences obtained, we found 1573 missense mutations in the spike gene, and 226 of them were within the receptor-binding domain (RBD) region that directly interacts with human ACE2. Modeling the interactions between SARS-CoV-2 spike mutants and ACE2 molecules showed that most of the 74 missense mutations in the RBD region of the interaction interface had little impact on spike binding to ACE2, whereas several within the spike RBD increased the binding affinity toward human ACE2 thus making the virus likely more contagious. On the other hand, modeling the interactions between animal ACE2 molecules and SARS-CoV-2 spike revealed that many pets and wild animals' ACE2 had a variable binding ability. Particularly, ACE2 of bamboo rat had stronger binding to SARS-CoV-2 spike protein, whereas that of mole, vole, Mus pahari, palm civet, and pangolin had a weaker binding compared to human ACE2. Our results provide structural insights into the impact on interactions of the SARS-CoV-2 spike mutants to human ACE2, and shed light on SARS-CoV-2 transmission in pets and wild animals, and possible clues to the intermediate host(s) for SARS-CoV-2.


Subject(s)
Angiotensin-Converting Enzyme 2/chemistry , COVID-19/veterinary , COVID-19/virology , Mutation, Missense , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Angiotensin-Converting Enzyme 2/genetics , Animals , Animals, Wild/genetics , Animals, Wild/virology , COVID-19/transmission , Computational Biology , Host Microbial Interactions/genetics , Host Specificity/genetics , Humans , Molecular Dynamics Simulation , Pandemics/veterinary , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/genetics , Pets/genetics , Pets/virology , Protein Interaction Domains and Motifs/genetics , Risk Factors
8.
BMC Med Genomics ; 14(1): 226, 2021 09 17.
Article in English | MEDLINE | ID: covidwho-1542114

ABSTRACT

BACKGROUND: Higher mortality of COVID-19 patients with lung disease is a formidable challenge for the health care system. Genetic association between COVID-19 and various lung disorders must be understood to comprehend the molecular basis of comorbidity and accelerate drug development. METHODS: Lungs tissue-specific neighborhood network of human targets of SARS-CoV-2 was constructed. This network was integrated with lung diseases to build a disease-gene and disease-disease association network. Network-based toolset was used to identify the overlapping disease modules and drug targets. The functional protein modules were identified using community detection algorithms and biological processes, and pathway enrichment analysis. RESULTS: In total, 141 lung diseases were linked to a neighborhood network of SARS-CoV-2 targets, and 59 lung diseases were found to be topologically overlapped with the COVID-19 module. Topological overlap with various lung disorders allows repurposing of drugs used for these disorders to hit the closely associated COVID-19 module. Further analysis showed that functional protein-protein interaction modules in the lungs, substantially hijacked by SARS-CoV-2, are connected to several lung disorders. FDA-approved targets in the hijacked protein modules were identified and that can be hit by exiting drugs to rescue these modules from virus possession. CONCLUSION: Lung diseases are clustered with COVID-19 in the same network vicinity, indicating the potential threat for patients with respiratory diseases after SARS-CoV-2 infection. Pathobiological similarities between lung diseases and COVID-19 and clinical evidence suggest that shared molecular features are the probable reason for comorbidity. Network-based drug repurposing approaches can be applied to improve the clinical conditions of COVID-19 patients.


Subject(s)
COVID-19/drug therapy , COVID-19/epidemiology , Drug Repositioning , Lung Diseases/epidemiology , Pandemics , SARS-CoV-2 , Algorithms , Antiviral Agents/therapeutic use , COVID-19/genetics , Comorbidity , Drug Discovery , Drug Repositioning/methods , Gene Regulatory Networks/drug effects , Host Microbial Interactions/drug effects , Host Microbial Interactions/genetics , Humans , Lung Diseases/drug therapy , Lung Diseases/genetics , Protein Interaction Maps/drug effects , Protein Interaction Maps/genetics , Systems Biology
9.
Genes (Basel) ; 12(11)2021 11 22.
Article in English | MEDLINE | ID: covidwho-1533885

ABSTRACT

Host genomic information, specifically genomic variations, may characterize susceptibility to disease and identify people with a higher risk of harm, leading to better targeting of care and vaccination. Italy was the epicentre for the spread of COVID-19 in Europe, the first country to go into a national lockdown and has one of the highest COVID-19 associated mortality rates. Qatar, on the other hand has a very low mortality rate. In this study, we compared whole-genome sequencing data of 14398 adults and Qatari-national to 925 Italian individuals. We also included in the comparison whole-exome sequence data from 189 Italian laboratory-confirmed COVID-19 cases. We focused our study on a curated list of 3619 candidate genes involved in innate immunity and host-pathogen interaction. Two population-gene metric scores, the Delta Singleton-Cohort variant score (DSC) and Sum Singleton-Cohort variant score (SSC), were applied to estimate the presence of selective constraints in the Qatari population and in the Italian cohorts. Results based on DSC and SSC metrics demonstrated a different selective pressure on three genes (MUC5AC, ABCA7, FLNA) between Qatari and Italian populations. This study highlighted the genetic differences between Qatari and Italian populations and identified a subset of genes involved in innate immunity and host-pathogen interaction.


Subject(s)
COVID-19/genetics , Genetic Predisposition to Disease/genetics , Host Microbial Interactions/genetics , Adult , Alleles , COVID-19/epidemiology , Communicable Disease Control , Disease Susceptibility/metabolism , Exome/genetics , Female , Gene Frequency/genetics , Genetic Predisposition to Disease/epidemiology , Genetics, Population , Genomics/methods , Humans , Immunity, Innate/immunology , Italy/epidemiology , Male , Qatar/epidemiology , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Whole Exome Sequencing/methods , Whole Genome Sequencing/methods
10.
Biochem Biophys Res Commun ; 586: 87-92, 2022 01 01.
Article in English | MEDLINE | ID: covidwho-1525697

ABSTRACT

There is an urgent need to understand the functional effects of mutations in emerging variants of SARS-CoV-2. Variants of concern (alpha, beta, gamma and delta) acquired four patterns of spike glycoprotein mutations that enhance transmissibility and immune evasion: 1) mutations in the N-terminal domain (NTD), 2) mutations in the Receptor Binding Domain (RBD), 3) mutations at interchain contacts of the spike trimer, and 4) furin cleavage site mutations. Most distinguishing mutations among variants of concern are exhibited in the NTD, localized to sites of high structural flexibility. Emerging variants of interest such as mu, lambda and C.1.2 exhibit the same patterns of mutations as variants of concern. There is a strong likelihood that SARS-CoV-2 variants will continue to emerge with mutations in these defined patterns, thus providing a basis for the development of next line antiviral drugs and vaccine candidates.


Subject(s)
COVID-19/virology , Mutation , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Amino Acid Sequence , Antibodies, Neutralizing/biosynthesis , Antibodies, Viral/biosynthesis , COVID-19/immunology , COVID-19/transmission , Evolution, Molecular , Host Microbial Interactions/genetics , Host Microbial Interactions/immunology , Humans , Models, Molecular , Pandemics , Protein Conformation , Protein Interaction Domains and Motifs/genetics , Protein Interaction Domains and Motifs/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology
11.
PLoS Comput Biol ; 17(11): e1009560, 2021 11.
Article in English | MEDLINE | ID: covidwho-1523396

ABSTRACT

Severe acute respiratory coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, is of zoonotic origin. Evolutionary analyses assessing whether coronaviruses similar to SARS-CoV-2 infected ancestral species of modern-day animal hosts could be useful in identifying additional reservoirs of potentially dangerous coronaviruses. We reasoned that if a clade of species has been repeatedly exposed to a virus, then their proteins relevant for viral entry may exhibit adaptations that affect host susceptibility or response. We perform comparative analyses across the mammalian phylogeny of angiotensin-converting enzyme 2 (ACE2), the cellular receptor for SARS-CoV-2, in order to uncover evidence for selection acting at its binding interface with the SARS-CoV-2 spike protein. We uncover that in rodents there is evidence for adaptive amino acid substitutions at positions comprising the ACE2-spike interaction interface, whereas the variation within ACE2 proteins in primates and some other mammalian clades is not consistent with evolutionary adaptations. We also analyze aminopeptidase N (APN), the receptor for the human coronavirus 229E, a virus that causes the common cold, and find evidence for adaptation in primates. Altogether, our results suggest that the rodent and primate lineages may have had ancient exposures to viruses similar to SARS-CoV-2 and HCoV-229E, respectively.


Subject(s)
COVID-19/genetics , COVID-19/virology , Coronavirus Infections/genetics , Coronavirus Infections/virology , SARS-CoV-2/genetics , Adaptation, Physiological/genetics , Amino Acid Substitution , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/physiology , Animals , CD13 Antigens/genetics , CD13 Antigens/physiology , Common Cold/genetics , Common Cold/virology , Computational Biology , Coronavirus 229E, Human/genetics , Coronavirus 229E, Human/physiology , Evolution, Molecular , Genomics , Host Microbial Interactions/genetics , Host Microbial Interactions/physiology , Host Specificity/genetics , Host Specificity/physiology , Humans , Mammals/genetics , Mammals/virology , Phylogeny , Protein Interaction Domains and Motifs/genetics , Receptors, Virus/genetics , Receptors, Virus/physiology , SARS-CoV-2/physiology , Selection, Genetic , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/physiology , Virus Internalization
12.
J Virol ; 96(2): e0167821, 2022 01 26.
Article in English | MEDLINE | ID: covidwho-1511415

ABSTRACT

The positive-sense, single-stranded RNA genome SARS-CoV-2 harbors functionally important cis-acting elements governing critical aspects of viral gene expression. However, insights on how these elements sense various signals from the host cell and regulate viral protein synthesis are lacking. Here, we identified two novel cis-regulatory elements in SARS-CoV-2 ORF1a and S RNAs and describe their role in translational control of SARS-CoV-2. These elements are sequence-unrelated but form conserved hairpin structures (validated by NMR) resembling gamma activated inhibitor of translation (GAIT) elements that are found in a cohort of human mRNAs directing translational suppression in myeloid cells in response to IFN-γ. Our studies show that treatment of human lung cells with receptor-binding S1 subunit, S protein pseudotyped lentivirus, and S protein-containing virus-like particles triggers a signaling pathway involving DAP-kinase1 that leads to phosphorylation and release of the ribosomal protein L13a from the large ribosomal subunit. Released L13a forms a virus activated inhibitor of translation (VAIT) complex that binds to ORF1a and S VAIT elements, causing translational silencing. Translational silencing requires extracellular S protein (and its interaction with host ACE2 receptor), but not its intracellular synthesis. RNA-protein interaction analyses and in vitro translation experiments showed that GAIT and VAIT elements do not compete with each other, highlighting differences between the two pathways. Sequence alignments of SARS-CoV-2 genomes showed a high level of conservation of VAIT elements, suggesting their functional importance. This VAIT-mediated translational control mechanism of SARS-CoV-2 may provide novel targets for small molecule intervention and/or facilitate development of more effective mRNA vaccines. IMPORTANCE Specific RNA elements in the genomes of RNA viruses play important roles in host-virus interaction. For SARS-CoV-2, the mechanistic insights on how these RNA elements could sense the signals from the host cell are lacking. Here we report a novel relationship between the GAIT-like SARS-CoV-2 RNA element (called VAITs) and the signal generated from the host cell. We show that for SARS-CoV-2, the interaction of spike protein with ACE2 not only serves the purpose for viral entry into the host cell, but also transduces signals that culminate into the phosphorylation and the release of L13a from the large ribosomal subunit. We also show that this event leads to the translational arrest of ORF1a and S mRNAs in a manner dependent on the structure of the RNA elements. Translational control of viral mRNA by a host-cell generated signal triggered by viral protein is a new paradigm in the host-virus relationship.


Subject(s)
COVID-19 , Host Microbial Interactions , RNA, Viral/immunology , SARS-CoV-2 , A549 Cells , COVID-19/immunology , COVID-19/virology , Host Microbial Interactions/genetics , Host Microbial Interactions/immunology , Humans , Protein Binding , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Virus Internalization
13.
JCI Insight ; 6(24)2021 12 22.
Article in English | MEDLINE | ID: covidwho-1501860

ABSTRACT

SARS-CoV-2 promotes an imbalanced host response that underlies the development and severity of COVID-19. Infections with viruses are known to modulate transposable elements (TEs), which can exert downstream effects by modulating host gene expression, innate immune sensing, or activities encoded by their protein products. We investigated the impact of SARS-CoV-2 infection on TE expression using RNA-Seq data from cell lines and from primary patient samples. Using a bioinformatics tool, Telescope, we showed that SARS-CoV-2 infection led to upregulation or downregulation of TE transcripts, a subset of which differed from cells infected with SARS, Middle East respiratory syndrome coronavirus (MERS-CoV or MERS), influenza A virus (IAV), respiratory syncytial virus (RSV), and human parainfluenza virus type 3 (HPIV3). Differential expression of key retroelements specifically identified distinct virus families, such as Coronaviridae, with unique retroelement expression subdividing viral species. Analysis of ChIP-Seq data showed that TEs differentially expressed in SARS-CoV-2 infection were enriched for binding sites for transcription factors involved in immune responses and for pioneer transcription factors. In samples from patients with COVID-19, there was significant TE overexpression in bronchoalveolar lavage fluid and downregulation in PBMCs. Thus, although the host gene transcriptome is altered by infection with SARS-CoV-2, the retrotranscriptome may contain the most distinctive features of the cellular response to SARS-CoV-2 infection.


Subject(s)
COVID-19/genetics , Endogenous Retroviruses/genetics , Long Interspersed Nucleotide Elements/genetics , A549 Cells , Cell Line , Chromatin Immunoprecipitation Sequencing , Computational Biology , Coronavirus Infections/genetics , DNA Transposable Elements/genetics , Down-Regulation , Host Microbial Interactions/genetics , Humans , In Vitro Techniques , Influenza A virus , Influenza, Human/genetics , Middle East Respiratory Syndrome Coronavirus , Parainfluenza Virus 3, Human , RNA-Seq , Respiratory Syncytial Virus Infections/genetics , Respiratory Syncytial Viruses , Respirovirus Infections/genetics , Retroelements/genetics , SARS Virus , SARS-CoV-2 , Severe Acute Respiratory Syndrome/genetics , Transcriptome , Up-Regulation
14.
Nucleic Acids Res ; 50(D1): D817-D827, 2022 01 07.
Article in English | MEDLINE | ID: covidwho-1493884

ABSTRACT

Virus infections are huge threats to living organisms and cause many diseases, such as COVID-19 caused by SARS-CoV-2, which has led to millions of deaths. To develop effective strategies to control viral infection, we need to understand its molecular events in host cells. Virus related functional genomic datasets are growing rapidly, however, an integrative platform for systematically investigating host responses to viruses is missing. Here, we developed a user-friendly multi-omics portal of viral infection named as MVIP (https://mvip.whu.edu.cn/). We manually collected available high-throughput sequencing data under viral infection, and unified their detailed metadata including virus, host species, infection time, assay, and target, etc. We processed multi-layered omics data of more than 4900 viral infected samples from 77 viruses and 33 host species with standard pipelines, including RNA-seq, ChIP-seq, and CLIP-seq, etc. In addition, we integrated these genome-wide signals into customized genome browsers, and developed multiple dynamic charts to exhibit the information, such as time-course dynamic and differential gene expression profiles, alternative splicing changes and enriched GO/KEGG terms. Furthermore, we implemented several tools for efficiently mining the virus-host interactions by virus, host and genes. MVIP would help users to retrieve large-scale functional information and promote the understanding of virus-host interactions.


Subject(s)
Databases, Factual , Host Microbial Interactions , Virus Diseases , Animals , Chromatin Immunoprecipitation Sequencing , Gene Ontology , Genome, Viral , High-Throughput Nucleotide Sequencing , Host Microbial Interactions/genetics , Humans , Metadata , Sequence Analysis, RNA , Software , Transcriptome , User-Computer Interface , Virus Diseases/genetics , Virus Diseases/metabolism , Web Browser
15.
Viruses ; 13(10)2021 10 04.
Article in English | MEDLINE | ID: covidwho-1481009

ABSTRACT

The livestock industry is constantly threatened by viral disease outbreaks, including infections with zoonotic potential. While preventive vaccination is frequently applied, disease control and eradication also depend on strict biosecurity measures. Clustered regularly interspaced palindromic repeats (CRISPR) and associated proteins (Cas) have been repurposed as genome editors to induce targeted double-strand breaks at almost any location in the genome. Thus, CRISPR/Cas genome editors can also be utilized to generate disease-resistant or resilient livestock, develop vaccines, and further understand virus-host interactions. Genes of interest in animals and viruses can be targeted to understand their functions during infection. Furthermore, transgenic animals expressing CRISPR/Cas can be generated to target the viral genome upon infection. Genetically modified livestock can thereby reduce disease outbreaks and decrease zoonotic threats.


Subject(s)
Gene Editing/methods , Livestock/virology , Viruses/genetics , Animal Husbandry/methods , Animals , CRISPR-Cas Systems/genetics , Clustered Regularly Interspaced Short Palindromic Repeats/genetics , Genetic Engineering , Host Microbial Interactions/genetics , Virus Diseases/prevention & control , Viruses/pathogenicity
16.
Eur J Immunol ; 51(7): 1641-1651, 2021 07.
Article in English | MEDLINE | ID: covidwho-1473829

ABSTRACT

Emerging life-threatening viruses have posed great challenges to public health. It is now increasingly clear that epigenetics plays a role in shaping host-virus interactions and there is a great need for a more thorough understanding of these intricate interactions through the epigenetic lens, which may represent potential therapeutic opportunities in the clinic. In this review, we highlight the current understanding of the roles of key epigenetic regulators - chromatin remodeling and histone modification - in modulating chromatin openness during host defense against virus. We also discuss how the RNA modification m6A (N6-methyladenosine) affects fundamental aspects of host-virus interactions. We conclude with future directions for uncovering more detailed functions that epigenetic regulation exerts on both host cells and viruses during infection.


Subject(s)
Antiviral Agents/immunology , Epigenesis, Genetic/genetics , Epigenesis, Genetic/immunology , Immunity, Innate/genetics , Immunity, Innate/immunology , Animals , Chromatin/genetics , Chromatin/immunology , Histones/genetics , Histones/immunology , Host Microbial Interactions/genetics , Host Microbial Interactions/immunology , Humans , RNA Processing, Post-Transcriptional/genetics , RNA Processing, Post-Transcriptional/immunology
17.
Mol Syst Biol ; 17(10): e10387, 2021 10.
Article in English | MEDLINE | ID: covidwho-1478718

ABSTRACT

We need to effectively combine the knowledge from surging literature with complex datasets to propose mechanistic models of SARS-CoV-2 infection, improving data interpretation and predicting key targets of intervention. Here, we describe a large-scale community effort to build an open access, interoperable and computable repository of COVID-19 molecular mechanisms. The COVID-19 Disease Map (C19DMap) is a graphical, interactive representation of disease-relevant molecular mechanisms linking many knowledge sources. Notably, it is a computational resource for graph-based analyses and disease modelling. To this end, we established a framework of tools, platforms and guidelines necessary for a multifaceted community of biocurators, domain experts, bioinformaticians and computational biologists. The diagrams of the C19DMap, curated from the literature, are integrated with relevant interaction and text mining databases. We demonstrate the application of network analysis and modelling approaches by concrete examples to highlight new testable hypotheses. This framework helps to find signatures of SARS-CoV-2 predisposition, treatment response or prioritisation of drug candidates. Such an approach may help deal with new waves of COVID-19 or similar pandemics in the long-term perspective.


Subject(s)
COVID-19/immunology , Computational Biology/methods , Databases, Factual , SARS-CoV-2/immunology , Software , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/genetics , COVID-19/virology , Computer Graphics , Cytokines/genetics , Cytokines/immunology , Data Mining/statistics & numerical data , Gene Expression Regulation , Host Microbial Interactions/genetics , Host Microbial Interactions/immunology , Humans , Immunity, Cellular/drug effects , Immunity, Humoral/drug effects , Immunity, Innate/drug effects , Lymphocytes/drug effects , Lymphocytes/immunology , Lymphocytes/virology , Metabolic Networks and Pathways/genetics , Metabolic Networks and Pathways/immunology , Myeloid Cells/drug effects , Myeloid Cells/immunology , Myeloid Cells/virology , Protein Interaction Mapping , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Signal Transduction , Transcription Factors/genetics , Transcription Factors/immunology , Viral Proteins/genetics , Viral Proteins/immunology
18.
Gene ; 808: 145963, 2022 Jan 15.
Article in English | MEDLINE | ID: covidwho-1415409

ABSTRACT

As of July 2021, the outbreak of coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, has led to more than 200 million infections and more than 4.2 million deaths globally. Complications of severe COVID-19 include acute kidney injury, liver dysfunction, cardiomyopathy, and coagulation dysfunction. Thus, there is an urgent need to identify proteins and genetic factors associated with COVID-19 susceptibility and outcome. We comprehensively reviewed recent findings of host-SARS-CoV-2 interactome analyses. To identify genetic variants associated with COVID-19, we focused on the findings from genome and transcriptome wide association studies (GWAS and TWAS) and bioinformatics analysis. We described established human proteins including ACE2, TMPRSS2, 40S ribosomal subunit, ApoA1, TOM70, HLA-A, and PALS1 interacting with SARS-CoV-2 based on cryo-electron microscopy results. Furthermore, we described approximately 1000 human proteins showing evidence of interaction with SARS-CoV-2 and highlighted host cellular processes such as innate immune pathways affected by infection. We summarized the evidence on more than 20 identified candidate genes in COVID-19 severity. Predicted deleterious and disruptive genetic variants with possible effects on COVID-19 infectivity have been also summarized. These findings provide novel insights into SARS-CoV-2 biology and infection as well as potential strategies for development of novel COVID therapeutic targets and drug repurposing.


Subject(s)
COVID-19/metabolism , Host Microbial Interactions/genetics , SARS-CoV-2/metabolism , COVID-19/physiopathology , Computational Biology/methods , Cryoelectron Microscopy/methods , Crystallography, X-Ray/methods , Genome-Wide Association Study , Host Microbial Interactions/physiology , Host-Pathogen Interactions/genetics , Humans , Proteins/metabolism , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity
19.
Cell Mol Life Sci ; 78(21-22): 6735-6744, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1377320

ABSTRACT

Kallikrein-related peptidases (KLKs) or kallikreins have been linked to diverse (patho) physiological processes, such as the epidermal desquamation and inflammation, seminal clot liquefaction, neurodegeneration, and cancer. Recent mounting evidence suggests that KLKs also represent important regulators of viral infections. It is well-established that certain enveloped viruses, including influenza and coronaviruses, require proteolytic processing of their hemagglutinin or spike proteins, respectively, to infect host cells. Similarly, the capsid protein of the non-enveloped papillomavirus L1 should be proteolytically cleaved for viral uncoating. Consequently, extracellular or membrane-bound proteases of the host cells are instrumental for viral infections and represent potential targets for drug development. Here, we summarize how extracellular proteolysis mediated by the kallikreins is implicated in the process of influenza (and potentially coronavirus and papillomavirus) entry into host cells. Besides direct proteolytic activation of viruses, KLK5 and 12 promote viral entry indirectly through proteolytic cascade events, like the activation of thrombolytic enzymes that also can process hemagglutinin, while additional functions of KLKs in infection cannot be excluded. In the light of recent evidence, KLKs represent potential host targets for the development of new antivirals. Humanized animal models to validate their key functions in viral infections will be valuable.


Subject(s)
COVID-19/enzymology , COVID-19/virology , Host Microbial Interactions/physiology , Kallikreins/metabolism , SARS-CoV-2 , Virus Diseases/enzymology , Animals , Asthma/etiology , Coronavirus/genetics , Coronavirus/pathogenicity , Coronavirus/physiology , Host Microbial Interactions/genetics , Humans , Orthomyxoviridae/genetics , Orthomyxoviridae/pathogenicity , Orthomyxoviridae/physiology , Papillomavirus Infections/enzymology , Papillomavirus Infections/virology , Picornaviridae Infections/complications , Picornaviridae Infections/enzymology , Picornaviridae Infections/virology , Protein Processing, Post-Translational , Proteolysis , Rhinovirus/pathogenicity , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology , Varicella Zoster Virus Infection/enzymology , Varicella Zoster Virus Infection/virology , Viral Proteins/genetics , Viral Proteins/metabolism , Virus Diseases/virology , Virus Internalization
20.
Front Immunol ; 12: 700184, 2021.
Article in English | MEDLINE | ID: covidwho-1365542

ABSTRACT

Coronavirus disease 2019 (COVID-19), which has high incidence rates with rapid rate of transmission, is a pandemic that spread across the world, resulting in more than 3,000,000 deaths globally. Currently, several drugs have been used for the clinical treatment of COVID-19, such as antivirals (radecivir, baritinib), monoclonal antibodies (tocilizumab), and glucocorticoids (dexamethasone). Accumulating evidence indicates that long noncoding RNAs (lncRNAs) are essential regulators of virus infections and antiviral immune responses including biological processes that are involved in the regulation of COVID-19 and subsequent disease states. Upon viral infections, cellular lncRNAs directly regulate viral genes and influence viral replication and pathology through virus-mediated changes in the host transcriptome. Additionally, several host lncRNAs could help the occurrence of viral immune escape by inhibiting type I interferons (IFN-1), while others could up-regulate IFN-1 production to play an antiviral role. Consequently, understanding the expression and function of lncRNAs during severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection will provide insights into the development of lncRNA-based methods. In this review, we summarized the current findings of lncRNAs in the regulation of the strong inflammatory response, immune dysfunction and thrombosis induced by SARS-CoV-2 infection, discussed the underlying mechanisms, and highlighted the therapeutic challenges of COVID-19 treatment and its future research directions.


Subject(s)
COVID-19/immunology , Host Microbial Interactions/genetics , Immunity, Innate/genetics , RNA, Long Noncoding/metabolism , Thrombosis/immunology , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Biomarkers/analysis , COVID-19/complications , COVID-19/drug therapy , COVID-19/genetics , COVID-19 Testing/methods , Cytokines/genetics , Cytokines/metabolism , Gene Expression Regulation, Viral/drug effects , Gene Expression Regulation, Viral/immunology , Host Microbial Interactions/drug effects , Host Microbial Interactions/immunology , Humans , Immune Evasion/genetics , Pandemics/prevention & control , RNA, Long Noncoding/analysis , RNA, Long Noncoding/antagonists & inhibitors , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Signal Transduction/genetics , Signal Transduction/immunology , Thrombosis/genetics , Thrombosis/virology , Virus Replication/drug effects , Virus Replication/genetics , Virus Replication/immunology
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