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1.
American journal of translational research ; 14(4):2655-2667, 2022.
Article in English | EuropePMC | ID: covidwho-1837264

ABSTRACT

Purpose: To investigate changes in the production of IgM and IgG antibodies and the negative transformation of viral nucleic acids in COVID-19 patients after convalescent plasma therapy, and also to discuss the clinical therapeutic effect, so as to provide a basis for the treatment of COVID-19 using specific antibodies. Methods: The convalescent plasma of recovered patients from COVID-19 was used to treat other patients, and the levels of antibodies IgM and IgG and the nucleic acid genes ORF1ab and N in the patients were tested regularly for statistical comparison and analysis. Results: In general, the Ct value and concentration of IgM and IgG antibodies in the plasma infusion group were significantly higher (1-3 times higher) than those in the non-plasma infusion group, respectively, but these differences were not significant (P>0.05). However, the content of antibodies in severe patients in the plasma transfusion group was significantly higher than those in the non-plasma transfusion group at discharge, the results being statistically significant (P<0.05). Conclusions: The application of convalescent plasma significantly increases the antibody content in severe and critical inpatients, effectively enhances immune function, accelerates the clearance of virus and the nucleic acid negative conversion rate, and significantly promotes early improvement in COVID-19 patients.

2.
Infect Drug Resist ; 15: 1225-1234, 2022.
Article in English | MEDLINE | ID: covidwho-1775530

ABSTRACT

Purpose: Polymorphisms in MBL2 may contribute to the susceptibility to tuberculosis. The aim of the present study was to determine the associations of the polymorphisms of five loci (rs1800450, rs1800451, rs7096206, rs7095891, and rs11003125) in the MBL2 gene with susceptibility to tuberculosis and specific lineages of Mycobacterium tuberculosis causing tuberculosis in the Uyghur population of Xinjiang, China. Methods: From January 2019 to January 2020, we enrolled 170 Uyghur tuberculosis patients as the case group and 147 Uyghur staff with no clinical symptoms as the control group from four designated tuberculosis hospitals in southern Xinjiang, China. The polymorphisms of five loci in MBL2 of human were detected by sequencing. Whole-genome sequencing was applied in 68 M. tuberculosis isolates from the case group and the data were used to perform genealogy analysis. Results: The distributions of allele and genotype frequencies of five loci in MBL2 varied little between the case and control groups and varied little among the groups, including those infected with different lineages of M. tuberculosis and the control (except those of rs11003125), the P values were all >0.05. The distribution of alleles of rs11003125 was statistically different between patients infected with lineages 3 and 4 M. tuberculosis (χ 2=7.037, P=0.008). The C allele and CC genotype of rs11003125 were found to be protective factors against lineage 4 infection when compared to lineage 3 (ORs were 0.190 and 0.158, respectively; 95% confidence intervals were 0.053~0.690 and 0.025~0.999, respectively). Conclusion: Our results suggested that human's susceptibility to tuberculosis is affected both by the host genetic polymorphisms and the lineage of the M. tuberculosis that people were exposed to. However, due to the limitation of the sample size in the present study, larger sample size and more rigorous design should be guaranteed in future studies.

3.
Cell Rep ; 37(4): 109882, 2021 10 26.
Article in English | MEDLINE | ID: covidwho-1525720

ABSTRACT

Remdesivir (RDV), a nucleotide analog with broad-spectrum features, has exhibited effectiveness in COVID-19 treatment. However, the precise working mechanism of RDV when targeting the viral RNA-dependent RNA polymerase (RdRP) has not been fully elucidated. Here, we solve a 3.0-Å structure of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RdRP elongation complex (EC) and assess RDV intervention in polymerase elongation phase. Although RDV could induce an "i+3" delayed termination in meta-stable complexes, only pausing and subsequent elongation are observed in the EC. A comparative investigation using an enterovirus RdRP further confirms similar delayed intervention and demonstrates that steric hindrance of the RDV-characteristic 1'-cyano at the -4 position is responsible for the "i+3" intervention, although two representative Flaviviridae RdRPs do not exhibit similar behavior. A comparison of representative viral RdRP catalytic complex structures indicates that the product RNA backbone encounters highly conserved structural elements, highlighting the broad-spectrum intervention potential of 1'-modified nucleotide analogs in anti-RNA virus drug development.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/pharmacology , RNA-Dependent RNA Polymerase/drug effects , SARS-CoV-2/drug effects , Viral Proteins/drug effects , Adenosine Monophosphate/pharmacology , Alanine/pharmacology , COVID-19/drug therapy , Cryoelectron Microscopy , Humans , RNA, Viral/chemistry , RNA, Viral/drug effects , RNA-Dependent RNA Polymerase/chemistry , SARS-CoV-2/chemistry , Viral Proteins/chemistry , Virus Replication/drug effects
4.
Nat Commun ; 11(1): 5874, 2020 11 18.
Article in English | MEDLINE | ID: covidwho-1387320

ABSTRACT

Non-structural proteins (nsp) constitute the SARS-CoV-2 replication and transcription complex (RTC) to play a pivotal role in the virus life cycle. Here we determine the atomic structure of a SARS-CoV-2 mini RTC, assembled by viral RNA-dependent RNA polymerase (RdRp, nsp12) with a template-primer RNA, nsp7 and nsp8, and two helicase molecules (nsp13-1 and nsp13-2), by cryo-electron microscopy. Two groups of mini RTCs with different conformations of nsp13-1 are identified. In both of them, nsp13-1 stabilizes overall architecture of the mini RTC by contacting with nsp13-2, which anchors the 5'-extension of RNA template, as well as interacting with nsp7-nsp8-nsp12-RNA. Orientation shifts of nsp13-1 results in its variable interactions with other components in two forms of mini RTC. The mutations on nsp13-1:nsp12 and nsp13-1:nsp13-2 interfaces prohibit the enhancement of helicase activity achieved by mini RTCs. These results provide an insight into how helicase couples with polymerase to facilitate its function in virus replication and transcription.


Subject(s)
Betacoronavirus/chemistry , Betacoronavirus/physiology , Virus Replication , Betacoronavirus/genetics , Betacoronavirus/metabolism , Binding Sites , Cryoelectron Microscopy , Humans , Methyltransferases/chemistry , Methyltransferases/genetics , Methyltransferases/metabolism , Models, Molecular , Mutation , Protein Binding , Protein Conformation , RNA Helicases/chemistry , RNA Helicases/genetics , RNA Helicases/metabolism , RNA, Viral/metabolism , SARS-CoV-2 , Structure-Activity Relationship , Transcription, Genetic , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolism
5.
Cell ; 184(1): 184-193.e10, 2021 01 07.
Article in English | MEDLINE | ID: covidwho-1385213

ABSTRACT

Transcription of SARS-CoV-2 mRNA requires sequential reactions facilitated by the replication and transcription complex (RTC). Here, we present a structural snapshot of SARS-CoV-2 RTC as it transitions toward cap structure synthesis. We determine the atomic cryo-EM structure of an extended RTC assembled by nsp7-nsp82-nsp12-nsp132-RNA and a single RNA-binding protein, nsp9. Nsp9 binds tightly to nsp12 (RdRp) NiRAN, allowing nsp9 N terminus inserting into the catalytic center of nsp12 NiRAN, which then inhibits activity. We also show that nsp12 NiRAN possesses guanylyltransferase activity, catalyzing the formation of cap core structure (GpppA). The orientation of nsp13 that anchors the 5' extension of template RNA shows a remarkable conformational shift, resulting in zinc finger 3 of its ZBD inserting into a minor groove of paired template-primer RNA. These results reason an intermediate state of RTC toward mRNA synthesis, pave a way to understand the RTC architecture, and provide a target for antiviral development.


Subject(s)
Coronavirus RNA-Dependent RNA Polymerase/chemistry , Cryoelectron Microscopy , RNA, Messenger/chemistry , RNA, Viral/chemistry , SARS-CoV-2/chemistry , Viral Replicase Complex Proteins/chemistry , Amino Acid Sequence , Coronavirus/chemistry , Coronavirus/classification , Coronavirus/enzymology , Coronavirus RNA-Dependent RNA Polymerase/metabolism , Methyltransferases/metabolism , Models, Molecular , RNA Helicases/metabolism , RNA-Binding Proteins/chemistry , RNA-Binding Proteins/metabolism , SARS-CoV-2/enzymology , Sequence Alignment , Transcription, Genetic , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolism , Virus Replication
6.
Infect Dis Poverty ; 10(1): 62, 2021 May 07.
Article in English | MEDLINE | ID: covidwho-1220178

ABSTRACT

BACKGROUND: A local coronavirus disease 2019 (COVID-19) case confirmed on June 11, 2020 triggered an outbreak in Beijing, China after 56 consecutive days without a newly confirmed case. Non-pharmaceutical interventions (NPIs) were used to contain the source in Xinfadi (XFD) market. To rapidly control the outbreak, both traditional and newly introduced NPIs including large-scale management of high-risk populations and expanded severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PCR-based screening in the general population were conducted in Beijing. We aimed to assess the effectiveness of the response to the COVID-19 outbreak in Beijing's XFD market and inform future response efforts of resurgence across regions. METHODS: A modified susceptible-exposed-infectious-recovered (SEIR) model was developed and applied to evaluate a range of different scenarios from the public health perspective. Two outcomes were measured: magnitude of transmission (i.e., number of cases in the outbreak) and endpoint of transmission (i.e., date of containment). The outcomes of scenario evaluations were presented relative to the reality case (i.e., 368 cases in 34 days) with 95% Confidence Interval (CI). RESULTS: Our results indicated that a 3 to 14 day delay in the identification of XFD as the infection source and initiation of NPIs would have caused a 3 to 28-fold increase in total case number (31-77 day delay in containment). A failure to implement the quarantine scheme employed in the XFD outbreak for defined key population would have caused a fivefold greater number of cases (73 day delay in containment). Similarly, failure to implement the quarantine plan executed in the XFD outbreak for close contacts would have caused twofold greater transmission (44 day delay in containment). Finally, failure to implement expanded nucleic acid screening in the general population would have yielded 1.6-fold greater transmission and a 32 day delay to containment. CONCLUSIONS: This study informs new evidence that in form the selection of NPI to use as countermeasures in response to a COVID-19 outbreak and optimal timing of their implementation. The evidence provided by this study should inform responses to future outbreaks of COVID-19 and future infectious disease outbreak preparedness efforts in China and elsewhere.


Subject(s)
COVID-19/epidemiology , Beijing/epidemiology , COVID-19/transmission , COVID-19 Testing , China/epidemiology , Epidemiological Monitoring , Humans , Models, Statistical , Pandemics , Quarantine , SARS-CoV-2/isolation & purification
7.
Curr Med Sci ; 41(1): 31-38, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1084475

ABSTRACT

The outbreak of coronavirus disease 2019 (COVID-19) posed an unprecedented threat to health care providers (HCPs) in Wuhan, China, especially for nurses who were frequently exposed to infected or suspected patients. Limited information was available about the working experience of nurses in fighting against the pandemic. To learn the physical and psychological responses of nurses during the pandemic and explore the potential determinants, we conducted a large-scale survey in Wuhan. This multicenter cross-sectional study enrolled 5521 nurses who worked in designated hospitals, mobile cabins, or shelters during the pandemic. A structured online questionnaire was distributed to assess the physical discomforts, emotional distress and cognitive reactions of nurses at work, and the log-binomial regression analysis was performed to explore potential determinants. A considerable proportion of nurses had symptoms of physical discomforts [3677 (66.6%)] and emotional distress [4721 (85.5%)]. Nurses who were directly involved in the care of patients (i.e., care for severe patients: RR, 2.35; 95% CI, 1.95-2.84), with irregular work schedules (RR, 2.36; 95% CI, 1.95-2.87), and working overtime (RR, 1.34; 95% CI, 1.08-1.65) were at a higher risk for physical discomforts. Nurses who were directly involved in the care of patients (i.e., care for severe patients: RR, 1.78; 95% CI, 1.40-2.29), with irregular work schedules (RR, 3.39; 95% CI, 2.43-4.73), and working overtime (RR, 1.51; 95% CI, 1.12-2.04) were at a higher risk for emotional distress. Therefore, formulating reasonable work schedules and improving workforce systems are necessary to alleviate the physical and emotional distress of nurses during the pandemic.


Subject(s)
COVID-19/nursing , Nurses/psychology , Occupational Stress/psychology , Workload/psychology , Adult , COVID-19/psychology , China , Cross-Sectional Studies , Female , Humans , Male , Middle Aged , Surveys and Questionnaires
10.
SSRN; 2020.
Preprint | SSRN | ID: ppcovidwho-1418

ABSTRACT

Background: The outbreak of coronavirus disease 2019 (COVID-19) posed an unprecedented threat to health care providers (HCPs) in Wuhan, China, especially for nu

11.
Mol Psychiatry ; 26(1): 30-39, 2021 01.
Article in English | MEDLINE | ID: covidwho-766055

ABSTRACT

The global pandemic of COVID-19 is colliding with the epidemic of opioid use disorders (OUD) and other substance use disorders (SUD) in the United States (US). Currently, there is limited data on risks, disparity, and outcomes for COVID-19 in individuals suffering from SUD. This is a retrospective case-control study of electronic health records (EHRs) data of 73,099,850 unique patients, of whom 12,030 had a diagnosis of COVID-19. Patients with a recent diagnosis of SUD (within past year) were at significantly increased risk for COVID-19 (adjusted odds ratio or AOR = 8.699 [8.411-8.997], P < 10-30), an effect that was strongest for individuals with OUD (AOR = 10.244 [9.107-11.524], P < 10-30), followed by individuals with tobacco use disorder (TUD) (AOR = 8.222 ([7.925-8.530], P < 10-30). Compared to patients without SUD, patients with SUD had significantly higher prevalence of chronic kidney, liver, lung diseases, cardiovascular diseases, type 2 diabetes, obesity and cancer. Among patients with recent diagnosis of SUD, African Americans had significantly higher risk of COVID-19 than Caucasians (AOR = 2.173 [2.01-2.349], P < 10-30), with strongest effect for OUD (AOR = 4.162 [3.13-5.533], P < 10-25). COVID-19 patients with SUD had significantly worse outcomes (death: 9.6%, hospitalization: 41.0%) than general COVID-19 patients (death: 6.6%, hospitalization: 30.1%) and African Americans with COVID-19 and SUD had worse outcomes (death: 13.0%, hospitalization: 50.7%) than Caucasians (death: 8.6%, hospitalization: 35.2%). These findings identify individuals with SUD, especially individuals with OUD and African Americans, as having increased risk for COVID-19 and its adverse outcomes, highlighting the need to screen and treat individuals with SUD as part of the strategy to control the pandemic while ensuring no disparities in access to healthcare support.


Subject(s)
COVID-19/epidemiology , Electronic Health Records/statistics & numerical data , Substance-Related Disorders/epidemiology , African Americans/statistics & numerical data , COVID-19/mortality , Case-Control Studies , Comorbidity , Hospitalization/statistics & numerical data , Humans , Pandemics , Retrospective Studies , Risk Factors , SARS-CoV-2 , United States/epidemiology , /statistics & numerical data
13.
Cell ; 182(2): 417-428.e13, 2020 07 23.
Article in English | MEDLINE | ID: covidwho-342735

ABSTRACT

Nucleotide analog inhibitors, including broad-spectrum remdesivir and favipiravir, have shown promise in in vitro assays and some clinical studies for COVID-19 treatment, this despite an incomplete mechanistic understanding of the viral RNA-dependent RNA polymerase nsp12 drug interactions. Here, we examine the molecular basis of SARS-CoV-2 RNA replication by determining the cryo-EM structures of the stalled pre- and post- translocated polymerase complexes. Compared with the apo complex, the structures show notable structural rearrangements happening to nsp12 and its co-factors nsp7 and nsp8 to accommodate the nucleic acid, whereas there are highly conserved residues in nsp12, positioning the template and primer for an in-line attack on the incoming nucleotide. Furthermore, we investigate the inhibition mechanism of the triphosphate metabolite of remdesivir through structural and kinetic analyses. A transition model from the nsp7-nsp8 hexadecameric primase complex to the nsp12-nsp7-nsp8 polymerase complex is also proposed to provide clues for the understanding of the coronavirus transcription and replication machinery.


Subject(s)
Betacoronavirus/chemistry , Betacoronavirus/enzymology , RNA-Dependent RNA Polymerase/chemistry , Viral Nonstructural Proteins/chemistry , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/metabolism , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/chemistry , Alanine/metabolism , Alanine/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Catalytic Domain , Coronavirus RNA-Dependent RNA Polymerase , Cryoelectron Microscopy , Models, Chemical , Models, Molecular , RNA, Viral/metabolism , SARS-CoV-2 , Transcription, Genetic , Virus Replication
14.
Science ; 368(6492): 779-782, 2020 05 15.
Article in English | MEDLINE | ID: covidwho-47347

ABSTRACT

A novel coronavirus [severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2)] outbreak has caused a global coronavirus disease 2019 (COVID-19) pandemic, resulting in tens of thousands of infections and thousands of deaths worldwide. The RNA-dependent RNA polymerase [(RdRp), also named nsp12] is the central component of coronaviral replication and transcription machinery, and it appears to be a primary target for the antiviral drug remdesivir. We report the cryo-electron microscopy structure of COVID-19 virus full-length nsp12 in complex with cofactors nsp7 and nsp8 at 2.9-angstrom resolution. In addition to the conserved architecture of the polymerase core of the viral polymerase family, nsp12 possesses a newly identified ß-hairpin domain at its N terminus. A comparative analysis model shows how remdesivir binds to this polymerase. The structure provides a basis for the design of new antiviral therapeutics that target viral RdRp.


Subject(s)
Betacoronavirus/enzymology , RNA-Dependent RNA Polymerase/chemistry , RNA-Dependent RNA Polymerase/ultrastructure , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/ultrastructure , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/metabolism , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/metabolism , Alanine/pharmacology , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Catalytic Domain , Coronavirus RNA-Dependent RNA Polymerase , Cryoelectron Microscopy , Drug Design , Models, Molecular , Multiprotein Complexes/chemistry , Multiprotein Complexes/metabolism , Multiprotein Complexes/ultrastructure , Protein Conformation, beta-Strand , Protein Domains , RNA-Dependent RNA Polymerase/antagonists & inhibitors , RNA-Dependent RNA Polymerase/metabolism , SARS-CoV-2 , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/metabolism
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