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1.
J Virol ; 96(1): e0169521, 2022 01 12.
Article in English | MEDLINE | ID: covidwho-1816694

ABSTRACT

The replication of coronaviruses, including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and the recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is closely associated with the endoplasmic reticulum (ER) of infected cells. The unfolded protein response (UPR), which is mediated by ER stress (ERS), is a typical outcome in coronavirus-infected cells and is closely associated with the characteristics of coronaviruses. However, the interaction between virus-induced ERS and coronavirus replication is poorly understood. Here, we demonstrate that infection with the betacoronavirus porcine hemagglutinating encephalomyelitis virus (PHEV) induced ERS and triggered all three branches of the UPR signaling pathway both in vitro and in vivo. In addition, ERS suppressed PHEV replication in mouse neuro-2a (N2a) cells primarily by activating the protein kinase R-like ER kinase (PERK)-eukaryotic initiation factor 2α (eIF2α) axis of the UPR. Moreover, another eIF2α phosphorylation kinase, interferon (IFN)-induced double-stranded RNA-dependent protein kinase (PKR), was also activated and acted cooperatively with PERK to decrease PHEV replication. Furthermore, we demonstrate that the PERK/PKR-eIF2α pathways negatively regulated PHEV replication by attenuating global protein translation. Phosphorylated eIF2α also promoted the formation of stress granules (SGs), which in turn repressed PHEV replication. In summary, our study presents a vital aspect of the host innate response to invading pathogens and reveals attractive host targets (e.g., PERK, PKR, and eIF2α) for antiviral drugs. IMPORTANCE Coronavirus diseases are caused by different coronaviruses of importance in humans and animals, and specific treatments are extremely limited. ERS, which can activate the UPR to modulate viral replication and the host innate response, is a frequent occurrence in coronavirus-infected cells. PHEV, a neurotropic betacoronavirus, causes nerve cell damage, which accounts for the high mortality rates in suckling piglets. However, it remains incompletely understood whether the highly developed ER in nerve cells plays an antiviral role in ERS and how ERS regulates viral proliferation. In this study, we found that PHEV infection induced ERS and activated the UPR both in vitro and in vivo and that the activated PERK/PKR-eIF2α axis inhibited PHEV replication through attenuating global protein translation and promoting SG formation. A better understanding of coronavirus-induced ERS and UPR activation may reveal the pathogenic mechanism of coronavirus and facilitate the development of new treatment strategies for these diseases.


Subject(s)
Betacoronavirus 1/physiology , Coronavirus Infections/metabolism , Eukaryotic Initiation Factor-2/metabolism , Virus Replication/physiology , eIF-2 Kinase/metabolism , Animals , Betacoronavirus 1/metabolism , Cell Line , Coronavirus Infections/virology , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum/ultrastructure , Endoplasmic Reticulum Stress , Mice , Phosphorylation , Protein Biosynthesis , Signal Transduction , Unfolded Protein Response
3.
Gene ; 2022.
Article in English | EuropePMC | ID: covidwho-1755706

ABSTRACT

Both feline coronavirus (FCoV) and SARS-CoV-2 are coronaviruses that infect cats and humans, respectively. However, cats have been shown to be susceptible to SARS-CoV-2, and FCoV also had been shown to infect human. To elucidate the relationship between FCoV and SARS-CoV-2, we highlight the main characteristics of the genome, the receptor usage, and the correlation of the receptor-binding domain (RBD) of spike proteins in FCoV and SARS-CoV-2. It is demonstrated that FCoV and SARS-CoV-2 are closely related to the main characteristics of the genome, receptor usage, and RBD of spike proteins with similar furin cleavage sites. In particular, the affinity of the conserved feline angiotensin-converting enzyme 2 (fACE2) receptor to the RBD of SARS-CoV-2 suggests that cats are susceptible to SARS-CoV-2. In addition, cross-species of coronaviruses between cats and humans or other domesticated animals are also discussed. This review sheds light on cats as potential intermediate hosts for SARS-CoV-2 transmission, and cross-species transmission or zoonotic infection of FCoV and SARS-CoV-2 between cats and humans was identified.

4.
Sports Med Health Sci ; 4(1): 61-69, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1751195

ABSTRACT

Under the condition of normalized epidemic, how athletes train and compete well has been in the spotlight. This article reported the symptom, hospitalization and training situation of seven confirmed cases of coronavirus-disease-2019 (COVID-19) among Chinese national teams. Moreover, the paper summarized the experience of Chinese national teams in terms of epidemic prevention and control, treatment of infection, and safe return to play. Through a scientific combination of medication and non-medical treatment, seven athletes were all discharged from the hospital. These discharged athletes underwent strict isolation and scientific training before returning to sports teams. Before returning to play, continuous monitoring of physical and mental condition was required. All seven athletes returned to play safely and performed excellently. As for hosting large-scale sporting events, the entire enclosed-loop management from immigration to competition was proposed in this paper. This study could serve as a standard of epidemic prevention and control, treatment for infection and safe return to play during competition and training around the world.

5.
Small Science ; n/a(n/a):2100124, 2022.
Article in English | Wiley | ID: covidwho-1739237

ABSTRACT

The current COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an enormous threat to public health. The SARS-CoV-2 3C-like protease (3CLpro), which is critical for viral replication and transcription, has been recognized as an ideal drug target. Herein, it is identified that three herbal compounds, Salvianolic acid A (SAA), (?)-Epigallocatechin gallate (EGCG), and Oridonin, directly inhibit the activity of SARS-CoV-2 3CLpro. Further, blocking SARS-CoV-2 infectivity by Oridonin is confirmed in cell-based experiments. By solving the crystal structure of 3CLpro in complex with Oridonin and comparing it to that of other ligands with 3CLpro, it is identified that Oridonin binds at the 3CLpro catalytic site by forming a C?S covalent bond, which is confirmed by mass spectrometry and kinetic study, blocking substrate binding through a nonpeptidomimetic covalent binding mode. Thus, Oridonin is a novel candidate to develop a new antiviral treatment for COVID-19.

6.
Nat Immunol ; 23(3): 423-430, 2022 03.
Article in English | MEDLINE | ID: covidwho-1713201

ABSTRACT

The global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic requires effective therapies against coronavirus disease 2019 (COVID-19), and neutralizing antibodies are a promising therapy. A noncompeting pair of human neutralizing antibodies (B38 and H4) blocking SARS-CoV-2 binding to its receptor, ACE2, have been described previously. Here, we develop bsAb15, a bispecific monoclonal antibody (bsAb) based on B38 and H4. bsAb15 has greater neutralizing efficiency than these parental antibodies, results in less selective pressure and retains neutralizing ability to most SARS-CoV-2 variants of concern (with more potent neutralizing activity against the Delta variant). We also selected for escape mutants of the two parental mAbs, a mAb cocktail and bsAb15, demonstrating that bsAb15 can efficiently neutralize all single-mAb escape mutants. Furthermore, prophylactic and therapeutic application of bsAb15 reduced the viral titer in infected nonhuman primates and human ACE2 transgenic mice. Therefore, this bsAb is a feasible and effective strategy to treat and prevent severe COVID-19.


Subject(s)
Antibodies, Bispecific/immunology , Antibodies, Monoclonal/immunology , Antibodies, Viral/immunology , SARS-CoV-2/immunology , Animals , Antibodies, Bispecific/chemistry , Antibodies, Bispecific/genetics , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/genetics , Antibodies, Neutralizing/genetics , Antibodies, Neutralizing/immunology , Antibodies, Viral/chemistry , Antibodies, Viral/genetics , COVID-19/immunology , COVID-19/pathology , COVID-19/prevention & control , COVID-19/virology , Cloning, Molecular , Disease Models, Animal , Dose-Response Relationship, Immunologic , Epitopes , Humans , Macaca mulatta , Mice , Neutralization Tests , Protein Engineering/methods , Structure-Activity Relationship
7.
iScience ; 25(3): 103934, 2022 Mar 18.
Article in English | MEDLINE | ID: covidwho-1693365

ABSTRACT

Here, we evaluated the immune properties of the HLA-A2 restricted CD8+ T cell epitopes containing mutations from B.1.1.7, and furthermore performed a comprehensive analysis of the SARS-CoV-2 specific CD8+ T cell responses from COVID-19 convalescent patients and SARS-CoV-2 vaccinees recognizing the ancestral Wuhan strain compared to B.1.1.7. First, most of the predicted CD8+ T cell epitopes showed proper binding with HLA-A2, whereas epitopes from B.1.1.7 had lower binding capability than those from the ancestral strain. In addition, these peptides could effectively induce the activation and cytotoxicity of CD8+ T cells. Our results further showed that at least two site mutations in B.1.1.7 resulted in a decrease in CD8+ T cell activation and a possible immune evasion, namely A1708D mutation in ORF1ab1707-1716 and I2230T mutation in ORF1ab2230-2238. Our current analysis provides information that contributes to the understanding of SARS-CoV-2-specific CD8+ T cell responses elicited by infection of mutated strains or vaccination.

8.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-327123

ABSTRACT

Since the first report on November 24, 2021, the Omicron SARS-CoV-2 variant is now overwhelmingly spreading across the world. Two SARS-CoV-2 inactivated vaccines (IAVs), one recombinant protein subunit vaccine (PRV), and one adenovirus-vectored vaccine (AdV) have been widely administrated in many countries including China to pursue herd immunity. Here we investigated cross-neutralizing activities in 341 human serum specimens elicited by full-course vaccinations with IAV, PRV and AdV, and by various vaccine boosters following prime IAV and AdV vaccinations. We found that all types of vaccines induced significantly lower neutralizing antibody titers against the Omicron variant than against the prototype strain. For prime vaccinations with IAV and AdV, heterologous boosters with AdV and PRV, respectively, elevated serum Omicron-neutralizing activities to the highest degrees. In a mouse model, we further demonstrated that among a series of variant-derived RBD-encoding mRNA vaccine boosters, it is only the Omicron booster that significantly enhanced Omicron neutralizing antibody titers compared with the prototype booster following a prime immunization with a prototype S-encoding mRNA vaccine candidate. In summary, our systematical investigations of various vaccine boosters inform potential booster administrations in the future to combat the Omicron variant.

9.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-323532

ABSTRACT

Background: We investigate the mental health status of all the staff members who worked for the designated hospital during the initial stage of COVID-19, so as to understand the severity of mental health problems, and analyze the risk factors. Methods: : Through the patients health questionnaire-9(PHQ-9) and panic disorder severity scales(PDSS), we surveyed the status of depression and panic disorder of the staff who participated in the prevention and treatment of COVID-19 in designated hospital in the early stage of epidemic. The data is described by the number of cases (percentage), median and interquartile range. The chi square test was used for categorical variables and the rank sum test was used for continuous variables. The risk factors of severe depression or panic disorder were analyzed by binary logistic regression test. Results: : Totally 702 questionnaires were sent out and 694(98.9%) was received and qualified, the median score of PHQ-9 among all the staff was 1 (IQR,0-4), 143(20.6%) of them had depression, 39 (5.6%) had serious depression;the median score of PDSS was 2 (IQR,0-5), 81 (11.7%) of them had panic disorder and 47(6.7%) of them had severe panic disorder;Among the people in different work lines, the first-line staff scored the highest: PHQ-9 score was 4 (0-8);PDSS score was 4 (1-9), which were significantly higher than the second-line and third-line staff (P<0.001). Multivariate logistic regression analysis showed that the adjusted risk of severe depression in first-line staff was 6.63 fold(P < 0.001);the risk of severe panic disorder was 2.62 fold (P=0.003) higher than that of non-first line group. Conclusions: : Many staff in the designated hospital for COVID-19 have mental health problems. Among them, first-line workers are a high-risk group with severe depression and panic disorder, and further psychological intervention is needed for them.

10.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-322991

ABSTRACT

Background: To compare clinical features between moderate and severe cases with COVID-19, and screen factors associated with disease severity. Methods: : Demographic and clinical data were compared between moderate and severe cases. Logistic regression was performed for prognostic factors. Results: : 163 patients (median age 65.0 (56.8-71.0) years, 78 (47.9%) females) were enrolled, including 87 (53.4%) severe and 76 (46.6%) moderate cases. 79 (90.8%) severe and 59 (77.6%) moderate cases had comorbidities, with hypertension and diabetes commonly presented. The most common symptoms were fever. Severe cases had higher lactate dehydrogenase (LDH), inflammatory cytokines and lymphopenia, eosinopenia on admission, and lower eosinophil and higher neutrophil counts from admission to day 13 and 19. Multivariable regression showed that neutrophilia, eosinopenia, high LDH and D-dimer were associated with severe COVID-19. In receiver operating characteristic curve analysis, LDH, eosinophil and neutrophil + eosinophil + LDH + D-dimer combination, with area under curve of 0.86, 0.76 and 0.93, predicted severe illness with high sensitivity (82.8%, 83.3%, 88.0%) and specificity (68.4%, 84.2%, 81.3%). Conclusions: : Eosinopenia, higher LDH and neutrophil + eosinophil + LDH + D-dimer combination on admission were powerful indicators of severe COVID-19. Dynamic changes of neutrophils and eosinophils may be used to evaluate disease progression.

11.
Emerg Microbes Infect ; 11(1): 306-309, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-1684435

ABSTRACT

Since the SARS-CoV-2 Omicron variant was first reported from South Africa, it has rapidly spread in over 100 countries. Only two cases infected by the Omicron variant were recently identified in China. The one case in Guangzhou has a relatively long incubation time and mild symptoms. Analysis of the complete viral genome sequence shows three missing Omicron unique mutations and one additional mutation in the newly characterized genome. These unique mutations may be related to the clinical presentation in this case.


Subject(s)
COVID-19 , SARS-CoV-2 , China , Humans , South Africa
12.
Viruses ; 14(1)2021 12 29.
Article in English | MEDLINE | ID: covidwho-1639272

ABSTRACT

Inactivated vaccines based on cell culture are very useful in the prevention and control of many diseases. The most popular strategy for the production of inactivated vaccines is based on monkey-derived Vero cells, which results in high productivity of the virus but has a certain carcinogenic risk due to non-human DNA contamination. Since human diploid cells, such as MRC-5 cells, can produce a safer vaccine, efforts to develop a strategy for inactivated vaccine production using these cells have been investigated using MRC-5 cells. However, most viruses do not replicate efficiently in MRC-5 cells. In this study, we found that rabies virus (RABV) infection activated a robust interferon (IFN)-ß response in MRC-5 cells but almost none in Vero cells, suggesting that the IFN response could be a key limiting factor for virus production. Treatment of the MRC-5 cells with IFN inhibitors increased RABV titers by 10-fold. Additionally, the RABV titer yield was improved five-fold when using IFN receptor 1 (IFNAR1) antibodies. As such, we established a stable IFNAR1-deficient MRC-5 cell line (MRC-5IFNAR1-), which increased RABV production by 6.5-fold compared to normal MRC-5 cells. Furthermore, in a pilot-scale production in 1500 square centimeter spinner flasks, utilization of the MRC-5IFNAR1- cell line or the addition of IFN inhibitors to MRC cells increased RABV production by 10-fold or four-fold, respectively. Thus, we successfully established a human diploid cell-based pilot scale virus production platform via inhibition of IFN response for rabies vaccines, which could also be used for other inactivated virus vaccine production.


Subject(s)
Diploidy , Interferons/pharmacology , Rabies Vaccines/immunology , Rabies virus , Rabies/prevention & control , Animals , Antibodies, Viral , Cell Line , Chlorocebus aethiops , Gene Expression , Humans , Interferons/genetics , Receptor, Interferon alpha-beta/genetics , Vaccines, Inactivated/immunology , Vero Cells
13.
J Virol ; 96(1): e0169521, 2022 01 12.
Article in English | MEDLINE | ID: covidwho-1621996

ABSTRACT

The replication of coronaviruses, including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and the recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is closely associated with the endoplasmic reticulum (ER) of infected cells. The unfolded protein response (UPR), which is mediated by ER stress (ERS), is a typical outcome in coronavirus-infected cells and is closely associated with the characteristics of coronaviruses. However, the interaction between virus-induced ERS and coronavirus replication is poorly understood. Here, we demonstrate that infection with the betacoronavirus porcine hemagglutinating encephalomyelitis virus (PHEV) induced ERS and triggered all three branches of the UPR signaling pathway both in vitro and in vivo. In addition, ERS suppressed PHEV replication in mouse neuro-2a (N2a) cells primarily by activating the protein kinase R-like ER kinase (PERK)-eukaryotic initiation factor 2α (eIF2α) axis of the UPR. Moreover, another eIF2α phosphorylation kinase, interferon (IFN)-induced double-stranded RNA-dependent protein kinase (PKR), was also activated and acted cooperatively with PERK to decrease PHEV replication. Furthermore, we demonstrate that the PERK/PKR-eIF2α pathways negatively regulated PHEV replication by attenuating global protein translation. Phosphorylated eIF2α also promoted the formation of stress granules (SGs), which in turn repressed PHEV replication. In summary, our study presents a vital aspect of the host innate response to invading pathogens and reveals attractive host targets (e.g., PERK, PKR, and eIF2α) for antiviral drugs. IMPORTANCE Coronavirus diseases are caused by different coronaviruses of importance in humans and animals, and specific treatments are extremely limited. ERS, which can activate the UPR to modulate viral replication and the host innate response, is a frequent occurrence in coronavirus-infected cells. PHEV, a neurotropic betacoronavirus, causes nerve cell damage, which accounts for the high mortality rates in suckling piglets. However, it remains incompletely understood whether the highly developed ER in nerve cells plays an antiviral role in ERS and how ERS regulates viral proliferation. In this study, we found that PHEV infection induced ERS and activated the UPR both in vitro and in vivo and that the activated PERK/PKR-eIF2α axis inhibited PHEV replication through attenuating global protein translation and promoting SG formation. A better understanding of coronavirus-induced ERS and UPR activation may reveal the pathogenic mechanism of coronavirus and facilitate the development of new treatment strategies for these diseases.


Subject(s)
Betacoronavirus 1/physiology , Coronavirus Infections/metabolism , Eukaryotic Initiation Factor-2/metabolism , Virus Replication/physiology , eIF-2 Kinase/metabolism , Animals , Betacoronavirus 1/metabolism , Cell Line , Coronavirus Infections/virology , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum/ultrastructure , Endoplasmic Reticulum Stress , Mice , Phosphorylation , Protein Biosynthesis , Signal Transduction , Unfolded Protein Response
15.
ISPRS International Journal of Geo-Information ; 10(10):659, 2021.
Article in English | ProQuest Central | ID: covidwho-1480789

ABSTRACT

Numerous studies have been devoted to uncovering the characteristics of resident density and urban mobility with multisource geospatial big data. However, little attention has been paid to the internal diversity of residents such as their occupations, which is a crucial aspect of urban vibrancy. This study aims to investigate the variation between individual and interactive influences of built environment factors on occupation mixture index (OMI) with a novel GeoDetector-based indicator. This study first integrated application (App) use and mobility patterns from cellphone data to portray residents’ occupations and evaluate the OMI in Guangzhou. Then, the mechanism of OMI distribution was analyzed with the GeoDetector model. Next, an optimized GeoDetector-based index, interactive effect variation ratio (IEVR) was proposed to quantify the variation between individual and interactive effects of factors. The results showed that land use mixture was the dominating factor, and that land use mixture, building density, floor area ratio, road density affected the OMI distribution directly. Some interesting findings were uncovered by IEVR. The influences of cultural inclusiveness and metro accessibility were less important in factor detector result, while they were found to be the most influential in an indirect way interacting with other built environment factors. The results suggested that both “hardware facilities” (land use mixture, accessibility) and “soft facilities” (cultural inclusiveness) should be considered in planning a harmonious urban employment space and sustainable city.

16.
Comput Struct Biotechnol J ; 19: 4868-4883, 2021.
Article in English | MEDLINE | ID: covidwho-1459507

ABSTRACT

There is an urgent need to develop effective treatments for coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The rapid spread of SARS-CoV-2 has resulted in a global pandemic that has not only affected the daily lives of individuals but also had a significant impact on the global economy and public health. Although extensive research has been conducted to identify inhibitors targeting SARS-CoV-2, there are still no effective treatment strategies to combat COVID-19. SARS-CoV-2 comprises two important proteolytic enzymes, namely, the papain-like proteinase, located within non-structural protein 3 (nsp3), and nsp5, both of which cleave large replicase polypeptides into multiple fragments that are required for viral replication. Moreover, a domain within nsp3, known as the macrodomain (Mac1), also plays an important role in viral replication. Inhibition of their functions should be able to significantly interfere with the replication cycle of the virus, and therefore these key proteins may serve as potential therapeutic targets. The functions of the above viral targets and their corresponding inhibitors have been summarized in the current review. This review provides comprehensive updates of nsp3 and nsp5 inhibitor development and would help advance the discovery of novel anti-viral therapeutics against SARS-CoV-2.

17.
J Virol ; 95(19): e0085121, 2021 09 09.
Article in English | MEDLINE | ID: covidwho-1403028

ABSTRACT

Uncoordinated 51-like kinase 1 (ULK1) is a well-characterized initiator of canonical autophagy under basal or pathological conditions. Porcine hemagglutinating encephalomyelitis virus (PHEV), a neurotropic betacoronavirus (ß-CoV), impairs ULK1 kinase but hijacks autophagy to facilitate viral proliferation. However, the machinery of PHEV-induced autophagy initiation upon ULK1 kinase deficiency remains unclear. Here, the time course of PHEV infection showed a significant accumulation of autophagosomes (APs) in nerve cells in vivo and in vitro. Utilizing ULK1-knockout neuroblastoma cells, we have identified that ULK1 is not essential for productive AP formation induced by PHEV. In vitro phosphorylation studies discovered that mTORC1-regulated ULK1 activation stalls during PHEV infection, whereas AP biogenesis was controlled by AMPK-driven BECN1 phosphorylation. A lack of BECN1 is sufficient to block LC3 lipidation and disrupt recruitment of the LC3-ATG14 complex. Moreover, BECN1 acts as a bona fide substrate for ULK1-independent neural autophagy, and ectopic expression of BECN1 somewhat enhances PHEV replication. These findings highlight a novel machinery of noncanonical autophagy independent of ULK1 that bypasses the conserved initiation circuit of AMPK-mTORC1-ULK1, providing new insights into the interplay between neurotropic ß-CoV and the host. IMPORTANCE The ongoing coronavirus disease 2019 (COVID-19) pandemic alongside the outbreaks of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) pose Betacoronavirus (ß-CoV) as a global public health challenge. Coronaviruses subvert, hijack, or utilize autophagy to promote proliferation, and thus, exploring the cross talk between ß-CoV and autophagy is of great significance in confronting future ß-CoV outbreaks. Porcine hemagglutinating encephalomyelitis virus (PHEV) is a highly neurotropic ß-CoV that invades the central nervous system (CNS) in pigs, but understanding of the pathogenesis for PHEV-induced neurological dysfunction is yet limited. Here, we discovered a novel regulatory principle of neural autophagy initiation during PHEV infection, where productive autophagosome (AP) biogenesis bypasses the multifaceted regulation of ULK1 kinase. The PHEV-triggered noncanonical autophagy underscores the complex interactions of virus and host and will help in the development of therapeutic strategies targeting noncanonical autophagy to treat ß-CoV disease.


Subject(s)
Autophagy-Related Protein-1 Homolog/genetics , Autophagy-Related Protein-1 Homolog/metabolism , Autophagy/physiology , Betacoronavirus 1/metabolism , Animals , Autophagosomes/metabolism , Beclin-1/metabolism , COVID-19 , Cell Line , Gene Knockout Techniques , Intracellular Signaling Peptides and Proteins/metabolism , Male , Mechanistic Target of Rapamycin Complex 1/metabolism , Mice , Mice, Inbred BALB C , Neurons/metabolism , Phosphorylation , SARS-CoV-2
19.
Brief Bioinform ; 22(6)2021 11 05.
Article in English | MEDLINE | ID: covidwho-1354275

ABSTRACT

For epidemic prevention and control, the identification of SARS-CoV-2 subpopulations sharing similar micro-epidemiological patterns and evolutionary histories is necessary for a more targeted investigation into the links among COVID-19 outbreaks caused by SARS-CoV-2 with similar genetic backgrounds. Genomic sequencing analysis has demonstrated the ability to uncover viral genetic diversity. However, an objective analysis is necessary for the identification of SARS-CoV-2 subpopulations. Herein, we detected all the mutations in 186 682 SARS-CoV-2 isolates. We found that the GC content of the SARS-CoV-2 genome had evolved to be lower, which may be conducive to viral spread, and the frameshift mutation was rare in the global population. Next, we encoded the genomic mutations in binary form and used an unsupervised learning classifier, namely PhenoGraph, to classify this information. Consequently, PhenoGraph successfully identified 303 SARS-CoV-2 subpopulations, and we found that the PhenoGraph classification was consistent with, but more detailed and precise than the known GISAID clades (S, L, V, G, GH, GR, GV and O). By the change trend analysis, we found that the growth rate of SARS-CoV-2 diversity has slowed down significantly. We also analyzed the temporal, spatial and phylogenetic relationships among the subpopulations and revealed the evolutionary trajectory of SARS-CoV-2 to a certain extent. Hence, our results provide a better understanding of the patterns and trends in the genomic evolution and epidemiology of SARS-CoV-2.


Subject(s)
COVID-19/epidemiology , Epidemics , Genomics , SARS-CoV-2/genetics , COVID-19/genetics , COVID-19/virology , Genetic Variation/genetics , Genome, Viral/genetics , Humans , Mutation/genetics , Phylogeny , SARS-CoV-2/pathogenicity
20.
Brief Bioinform ; 22(2): 1122-1136, 2021 03 22.
Article in English | MEDLINE | ID: covidwho-1352120

ABSTRACT

Temperature plays a significant role in the survival and transmission of SARS-CoV (severe acute respiratory syndrome coronavirus) and SARS-CoV-2. To reveal the binding differences of SARS-CoV and SARS-CoV-2 receptor-binding domains (RBDs) to angiotensin-converting enzyme 2 (ACE2) at different temperatures at atomic level, 20 molecular dynamics simulations were carried out for SARS-CoV and SARS-CoV-2 RBD-ACE2 complexes at five selected temperatures, i.e. 200, 250, 273, 300 and 350 K. The analyses on structural flexibility and conformational distribution indicated that the structure of the SARS-CoV-2 RBD was more stable than that of the SARS-CoV RBD at all investigated temperatures. Then, molecular mechanics Poisson-Boltzmann surface area and solvated interaction energy approaches were combined to estimate the differences in binding affinity of SARS-CoV and SARS-CoV-2 RBDs to ACE2; it is found that the binding ability of ACE2 to the SARS-CoV-2 RBD was stronger than that to the SARS-CoV RBD at five temperatures, and the main reason for promoting such binding differences is electrostatic and polar interactions between RBDs and ACE2. Finally, the hotspot residues facilitating the binding of SARS-CoV and SARS-CoV-2 RBDs to ACE2, the key differential residues contributing to the difference in binding and the interaction mechanism of differential residues that exist at all investigated temperatures were analyzed and compared in depth. The current work would provide a molecular basis for better understanding of the high infectiousness of SARS-CoV-2 and offer better theoretical guidance for the design of inhibitors targeting infectious diseases caused by SARS-CoV-2.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , SARS-CoV-2/metabolism , Amino Acid Sequence , Angiotensin-Converting Enzyme 2/chemistry , Cluster Analysis , Humans , Molecular Dynamics Simulation , Principal Component Analysis , Protein Binding , Sequence Homology, Amino Acid , Temperature
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