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1.
Travel Med Infect Dis ; 49: 102366, 2022 May 31.
Article in English | MEDLINE | ID: covidwho-1867829
2.
Signal Transduct Target Ther ; 7(1): 139, 2022 04 27.
Article in English | MEDLINE | ID: covidwho-1815514

ABSTRACT

The SARS-CoV-2 Omicron variant shows substantial resistance to neutralization by infection- and vaccination-induced antibodies, highlighting the demands for research on the continuing discovery of broadly neutralizing antibodies (bnAbs). Here, we developed a panel of bnAbs against Omicron and other variants of concern (VOCs) elicited by vaccination of adenovirus-vectored COVID-19 vaccine (Ad5-nCoV). We also investigated the human longitudinal antibody responses following vaccination and demonstrated how the bnAbs evolved over time. A monoclonal antibody (mAb), named ZWD12, exhibited potent and broad neutralization against SARS-CoV-2 variants Alpha, Beta, Gamma, Kappa, Delta, and Omicron by blocking the spike protein binding to the angiotensin-converting enzyme 2 (ACE2) and provided complete protection in the challenged prophylactic and therapeutic K18-hACE2 transgenic mouse model. We defined the ZWD12 epitope by determining its structure in complex with the spike (S) protein via cryo-electron microscopy. This study affords the potential to develop broadly therapeutic mAb drugs and suggests that the RBD epitope bound by ZWD12 is a rational target for the design of a broad spectrum of vaccines.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Antibodies, Monoclonal/genetics , Antibodies, Viral , Broadly Neutralizing Antibodies , COVID-19/prevention & control , COVID-19 Vaccines/genetics , Cryoelectron Microscopy , Epitopes , Humans , Mice , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Vaccination , Viral Envelope Proteins
3.
Cell Discov ; 8(1): 36, 2022 Apr 21.
Article in English | MEDLINE | ID: covidwho-1805604

ABSTRACT

The emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants of concern, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529) has aroused concerns over their increased infectivity and transmissibility, as well as decreased sensitivity to SARS-CoV-2-neutralizing antibodies (NAbs) and the current coronavirus disease 2019 (COVID-19) vaccines. Such exigencies call for the development of pan-sarbecovirus vaccines or inhibitors to combat the circulating SARS-CoV-2 NAb-escape variants and other sarbecoviruses. In this study, we isolated a broadly NAb against sarbecoviruses named GW01 from a donor who recovered from COVID-19. Cryo-EM structure and competition assay revealed that GW01 targets a highly conserved epitope in a wide spectrum of different sarbecoviruses. However, we found that GW01, the well-known sarbecovirus NAb S309, and the potent SARS-CoV-2 NAbs CC12.1 and REGN10989 only neutralize about 90% of the 56 tested currently circulating variants of SARS-CoV-2 including Omicron. Therefore, to improve efficacy, we engineered an IgG-like bispecific antibody GW01-REGN10989 (G9) consisting of single-chain antibody fragments (scFv) of GW01 and REGN10989. We found that G9 could neutralize 100% of NAb-escape mutants (23 out of 23), including Omicron variant, with a geometric mean (GM) 50% inhibitory concentration of 8.8 ng/mL. G9 showed prophylactic and therapeutic effects against SARS-CoV-2 infection of both the lung and brain in hACE2-transgenic mice. Site-directed mutagenesis analyses revealed that GW01 and REGN10989 bind to the receptor-binding domain in different epitopes and from different directions. Since G9 targets the epitopes for both GW01 and REGN10989, it was effective against variants with resistance to GW01 or REGN10989 alone and other NAb-escape variants. Therefore, this novel bispecific antibody, G9, is a strong candidate for the treatment and prevention of infection by SARS-CoV-2, NAb-escape variants, and other sarbecoviruses that may cause future emerging or re-emerging coronavirus diseases.

4.
Curr Opin Struct Biol ; 74: 102388, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1796139

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged as a public health crisis and led to tremendous economic devastation. The spike protein (S) of SARS-CoV-2 hijacks the angiotensin converting enzyme 2 (ACE2) as a receptor for virus entry, representing the initial step of viral infection. S is one of the major targets for development of the antiviral drugs, antibodies, and vaccines. ACE2 is a peptidase that plays a physiologically important role in the renin-angiotensin system. Concurrently, it also forms dimer of heterodimer with the neutral amino acid transporter B0AT1 to regulate intestinal amino acid metabolism. The symptoms of COVID-19 are closely correlated with the physiological functions of ACE2. In this review, we summarize the functional and structural studies on ACE2, B0AT1, and their complex with S of SARS-CoV-2, providing insights into the various symptoms caused by viral infection and the development of therapeutic strategies.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Angiotensin-Converting Enzyme 2 , Humans , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/metabolism , Protein Binding , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism
5.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-329546

ABSTRACT

Purpose: The immunogenicity of SARS-CoV-2 vaccines is poor in kidney transplant recipients (KTRs). The factors related to poor immunogenicity to vaccination in KTRs are not well defined. Methods An observational study was conducted in KTRs and healthy individuals who had received two doses of SARS-CoV-2 inactivated vaccine. IgG antibodies against the receptor-binding domain found in the S1 subunit of the spike protein, and against nucleocapsid protein were measured using enzyme-linked immunosorbent assay. Receptor-binding domain (RBD)-angiotensin-converting enzyme 2 interaction-blocking antibodies were measured using commercial kits. T cell responses against the spike and nucleocapsid proteins were detected using enzyme-linked immunosorbent spot assay. Results No severe adverse effects were observed in KTRs after first or second dose of SARS-CoV-2 inactivated vaccine. IgG antibodies against the receptor- binding domain, and nucleocapsid protein were not effectively induced in a majority of KTRs after second dose of inactivated vaccine. Specific T cell immunity response was detectable in 32%-40% KTRs after second doses of inactivated vaccine. KTRs who developed specific T cell immunity were more likely to be female, and have lower levels of total bilirubin, unconjugated bilirubin, and blood tacrolimus concentration. Multivariate logistic regression analysis found that blood unconjugated bilirubin was significantly negatively associated with SARS-CoV-2 specific T cell immunity response in k KTRs. Conclusions Specific T cell immunity response could be induced in 32%-40% KTRs after two doses of inactivated vaccine. Blood unconjugated bilirubin was negatively associated with specific cellular immunity response in KTRs following vaccination.

6.
Cell Discov ; 8(1): 16, 2022 Feb 15.
Article in English | MEDLINE | ID: covidwho-1692632

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) continue to wreak havoc across the globe. Higher transmissibility and immunologic resistance of VOCs bring unprecedented challenges to epidemic extinguishment. Here we describe a monoclonal antibody, 2G1, that neutralizes all current VOCs and has surprising tolerance to mutations adjacent to or within its interaction epitope. Cryo-electron microscopy structure showed that 2G1 bound to the tip of receptor binding domain (RBD) of spike protein with small contact interface but strong hydrophobic effect, which resulted in nanomolar to sub-nanomolar affinities to spike proteins. The epitope of 2G1 on RBD partially overlaps with angiotensin converting enzyme 2 (ACE2) interface, which enables 2G1 to block interaction between RBD and ACE2. The narrow binding epitope but high affinity bestow outstanding therapeutic efficacy upon 2G1 that neutralized VOCs with sub-nanomolar half maximal inhibitory concentration in vitro. In SARS-CoV-2, Beta or Delta variant-challenged transgenic mice and rhesus macaque models, 2G1 protected animals from clinical illness and eliminated viral burden, without serious impact to animal safety. Mutagenesis experiments suggest that 2G1 is potentially capable of dealing with emerging SARS-CoV-2 variants in the future. This report characterized the therapeutic antibodies specific to the tip of spike against SARS-CoV-2 variants and highlights the potential clinical applications as well as for developing vaccine and cocktail therapy.

7.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-312644

ABSTRACT

Background: High-flow nasal cannula (HFNC) oxygen therapy provides effective respiratory support in patients with hypoxemic respiratory failure. However, the efficacy of HFNC for patients with COVID-19 has not been established. This study was performed to assess the efficacy of HFNC for patients with COVID-19 and describe early predictors of HFNC treatment success in order to develop a prediction tool that accurately identifies the need for invasive mechanical ventilation (IMV). Methods: : We retrospectively reviewed the records of patients with COVID-19 who underwent HFNC in 2 hospitals in Wuhan between 1 January and 1 March 2020. Overall survival, the success rate of HFNC treatment and respiratory variables to predict the outcome of HFNC treatment were evaluated. Results: : A total of 105 patients were analyzed. Of these, 65 patients (61.9%) showed improved oxygenation and were successfully withdrawn from HFNC. The oxygenation index (PaO 2 /FiO 2 ), Oxygen saturation index (SpO 2 /FiO 2 ) and respiratory rate-oxygenation index (ROX index: SpO 2 /FiO 2 *RR) at 6h, 12h and 24h of HFNC initiation were closely related to the prognosis. The best predictor was the ROX index at 24h after initiating HFNC (area under the receiver operating characteristic curve, 0.874). In the multivariate logistic regression analysis, young age, gender of female, and lower SOFA score all have predictive value, while a ROX index greater than 6.10 at 24 h after initiation was significantly associated with HFNC success (OR, 104.212;95% CI, 11.399-952.757;p <0.001). Conclusions: : Our study indicated that HFNC was an effective way of respiratory support in the treatment of severe COVID-19. The ROX index greater than 6.10 at 24 h after initiating HFNC was a good predictor of successful HFNC treatment.

8.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-310217

ABSTRACT

Background: The coronavirus disease 2019 (COVID-19) pandemic has led to surges in the demand for extracorporeal membrane oxygenation (ECMO) therapy. However, little in-depth evidence is known about the application of ECMO therapy in COVID-19 patients. Methods This retrospective multicenter cohort study included 88 patients who had been diagnosed with COVID-19 and received ECMO therapy at seven designated hospitals in Wuhan, China. The clinical characteristics, laboratory examinations, treatments, and outcomes were extracted from electronic medical records and compared between weaned and non-weaned ECMO patients. The patients were followed until June 30, 2020. Logistic regression analyses were performed to identify the risk factors associated with unsuccessful ECMO weaning. Propensity score matching was used to match patients who received veno-venous ECMO with those who received invasive mechanical ventilation (IMV)-only therapy. The primary endpoint, 120-day all-cause mortality after intensive care unit (ICU) admission during hospitalization, was compared using a mixed-effect Cox model. Results Of 88 patients who received ECMO therapy, 27 and 61 patients were and were not successfully weaned from ECMO, respectively. Additionally, 15, 15, and 65 patients were further weaned from IMV, discharged from hospital, or died during hospitalization, respectively. A lymphocyte count ≤ 0.5 × 10 9 /L and D-dimer concentration > 4 × the upper limit of normal at ICU admission, a peak PaCO 2  > 60 mmHg at 24 hours before ECMO initiation, and no tracheotomy performed during the ICU stay were independently associated with lower odds of ECMO weaning. In the propensity score-matched analysis, a mixed-effect Cox model detected a lower hazard ratio for 120-day all-cause mortality after ICU admission during hospitalization in the ECMO group, as compared with the IMV-only group. Conclusion Patients in Wuhan who received ECMO therapy had a relatively high mortality rate. This outcome may be largely attributable to resource-limited situations during the COVID-19 outbreak. In future, the presence of lymphocytopenia and higher D-dimer concentrations at ICU admission and hypercapnia at 24 hours before ECMO initiation could help to identify patients with a poor prognosis. Moreover, tracheotomy could facilitate weaning from ECMO. Despite the high mortality, ECMO was associated with improved outcomes relative to IMV-only therapy in critically ill COVID-19 patients.

9.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-308149

ABSTRACT

The COVID-19 (formerly, 2019-nCoV) epidemic has become a global health emergency, as such, WHO declared PHEIC. China has taken the most hit since the outbreak of the virus, which could be dated as far back as late November by some experts. It was not until January 23rd that the Wuhan government finally recognized the severity of the epidemic and took a drastic measure to curtain the virus spread by closing down all transportation connecting the outside world. In this study, we seek to answer a few questions: How did the virus get spread from the epicenter Wuhan city to the rest of the country? To what extent did the measures, such as, city closure and community quarantine, help controlling the situation? More importantly, can we forecast any significant future development of the event had some of the conditions changed? By collecting and visualizing publicly available data, we first show patterns and characteristics of the epidemic development;we then employ a mathematical model of disease transmission dynamics to evaluate the effectiveness of some epidemic control measures, and more importantly, to offer a few tips on preventive measures.

10.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-325365

ABSTRACT

Background: The National Chest Pain Center Accreditation Program (CHANGE) is the first hospital-based, multifaceted, nationwide quality improvement (QI) initiative, to monitor and improve quality of ST-segment elevation myocardial infarction (STEMI) care in China. The QI initiatives, as implementation strategies, include a bundle of evidence-based interventions adapted for implementation in China. During the pandemic of coronavirus disease 2019 (COVID-19), fear of infection with severe acute respiratory syndrome coronavirus 2, national lockdowns, and altered health care priorities have highlighted the program’s importance in improving STEMI care quality. This study aims to minimize the adverse impact of the COVID-19 pandemic on the quality of STEMI care, by developing interventions that optimize the QI initiatives, implementing and evaluating the optimized QI initiatives, and developing scale-up activities of the optimized QI initiatives in response to COVID-19 and other public health emergencies. Methods: : A stepped wedge cluster randomized control trial will be conducted in three selected cities of China: Wuhan, Suzhou, and Shenzhen. Two districts have been randomly selected in each city, yielding a total of 24 registered hospitals. This study will conduct a rollout in these hospitals every 3 months. The 24 hospitals will be randomly assigned to four clusters, and each cluster will commence the intervention (optimized QI initiatives) at one of the four steps. We will conduct hospital-based assessments, questionnaire surveys among health care providers, community-based household surveys, and key informant interviews during the trial. All outcome measures will be organized using the RE-AIM (reach, effectiveness, adoption, implementation, maintenance) framework, including implementation outcomes, service outcomes (e.g., treatment time), and patient outcomes (e.g., in-hospital mortality and 1-year complication). The Consolidated Framework for Implementation Research framework will be used to identify factors that influence implementation of the optimized QI interventions. Discussion: The study findings could be translated into a systematic solution to implementing QI initiatives in response to COVID-19 and future potential major public health emergencies. Such actionable knowledge is critical for implementors of scale-up activities in low- and middle-income settings. Trial registration: This study was registered in the Chinese Clinical Trial Registry (ChiCTR 2100043319), registered 10 February 2021

11.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-323688

ABSTRACT

The current coronavirus disease 2019 (COVID-19) pandemic presents a global public health challenge. The viral pathogen responsible, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), binds to a host receptor ACE2 through its spike (S) glycoprotein, which mediates membrane fusion and virus entry. Although the role of ACE2 as a receptor for SARS-CoV-2 is clear, studies have shown that ACE2 expression across different human tissues is extremely low, especially in pulmonary and bronchial cells. Thus, other host receptors and/or co-receptors that promote the entry of SARS-CoV-2 into cells of the respiratory system might exist. In this study, we have identified tyrosine-protein kinase receptor UFO (AXL), specifically interacts with SARS-CoV-2 S on the host cell membrane. When overexpressed in cells that do not highly express either AXL or ACE2, AXL promotes virus entry as efficiently as ACE2. Strikingly, deleting AXL, but not ACE2, significantly reduces infection of pulmonary cells by the SARS-CoV-2 virus pseudotype. Soluble human recombinant AXL, but not ACE2, blocks SARS-CoV-2 virus pseudotype infection in pulmonary cells. Taken together, our findings suggest AXL may play an important role in promoting SARS-CoV-2 infection of the human respiratory system and is a potential target in future clinical intervention strategies.

12.
Nucleic Acids Res ; 50(7): e39, 2022 04 22.
Article in English | MEDLINE | ID: covidwho-1594198

ABSTRACT

GWASs have identified numerous genetic variants associated with a wide variety of diseases, yet despite the wide availability of genetic testing the insights that would enhance the interpretability of these results are not widely available to members of the public. As a proof of concept and demonstration of technological feasibility, we developed PAGEANT (Personal Access to Genome & Analysis of Natural Traits), usable through Graphical User Interface or command line-based version, aiming to serve as a protocol and prototype that guides the overarching design of genetic reporting tools. PAGEANT is structured across five core modules, summarized by five Qs: (i) quality assurance of the genetic data; (ii) qualitative assessment of genetic characteristics; (iii) quantitative assessment of health risk susceptibility based on polygenic risk scores and population reference; (iv) query of third-party variant databases (e.g. ClinVAR and PharmGKB) and (v) quick Response code of genetic variants of interest. Literature review was conducted to compare PAGEANT with academic and industry tools. For 2504 genomes made publicly available through the 1000 Genomes Project, we derived their genomic characteristics for a suite of qualitative and quantitative traits. One exemplary trait is susceptibility to COVID-19, based on the most up-to-date scientific findings reported.


Subject(s)
Genome, Human , Software , COVID-19/epidemiology , COVID-19/genetics , Genetic Variation , Genome-Wide Association Study , Genomics , Humans
13.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-296092

ABSTRACT

The recurrent outbreak of coronaviruses and variants underscores the need for broadly reactive antivirals and vaccines. Here, a novel broad-spectrum human antibody named 76E1 was isolated from a COVID-19 convalescent patient and showed broad neutralization activity against multiple α- and β-coronaviruses, including the SARS-CoV-2 variants and also exhibited the binding breath to peptides containing the epitope from γ- and δ- coronaviruses. 76E1 cross-protects mice from SARS-CoV-2 and HCoV-OC43 infection in both prophylactic and treatment models. The epitope including the fusion peptide and S2’ cleavage site recognized by 76E1 was significantly conserved among α-, β-, γ- and δ- coronaviruses. We uncovered a novel mechanism of antibody neutralization that the epitope of 76E1 was proportionally less exposed in the prefusion trimeric structure of spike protein but could be unmasked by binding to the receptor ACE2. Once the epitope exposed, 76E1 inhibited S2’ cleavage, thus blocked the membrane fusion process. Our data demonstrate a key epitope targeted by broadly-neutralizing antibodies and will guide next-generation epitope-based pan-coronavirus vaccine design.

14.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-294971

ABSTRACT

GWASs have identified numerous genetic variants associated with a wide variety of diseases, yet despite the wide availability of genetic testing the insights that would enhance the interpretability of these results are not widely available to members of the public. As a proof of concept and demonstration of technological feasibility, we developed PAGEANT ( P ersonal A ccess to Ge nome & A nalysis of N atural T raits), usable through Graphical User Interface or command line-based version, aiming to serve as a protocol and prototype that guides the overarching design of genetic reporting tools. PAGEANT is structured across five core modules, summarized by five Qs: (1) Quality assurance of the genetic data;(2) Qualitative assessment of genetic characteristics;(3) Quantitative assessment of health risk susceptibility based on polygenic risk scores and population reference;(4) Query of third-party variant databases (e.g., ClinVAR and PharmGKB);and (5) Quick Response code of genetic variants of interest. Literature review was conducted to compare PAGEANT with academic and industry tools. For 2,504 genomes made publicly available through the 1,000 Genomes Project, we derived their genomic characteristics for a suite of qualitative and quantitative traits. One exemplary trait is susceptibility to COVID-19, based on the most up-to-date scientific findings reported.

15.
Signal Transduct Target Ther ; 6(1): 315, 2021 08 25.
Article in English | MEDLINE | ID: covidwho-1442755

ABSTRACT

The evolution of coronaviruses, such as SARS-CoV-2, makes broad-spectrum coronavirus preventional or therapeutical strategies highly sought after. Here we report a human angiotensin-converting enzyme 2 (ACE2)-targeting monoclonal antibody, 3E8, blocked the S1-subunits and pseudo-typed virus constructs from multiple coronaviruses including SARS-CoV-2, SARS-CoV-2 mutant variants (SARS-CoV-2-D614G, B.1.1.7, B.1.351, B.1.617.1, and P.1), SARS-CoV and HCoV-NL63, without markedly affecting the physiological activities of ACE2 or causing severe toxicity in ACE2 "knock-in" mice. 3E8 also blocked live SARS-CoV-2 infection in vitro and in a prophylactic mouse model of COVID-19. Cryo-EM and "alanine walk" studies revealed the key binding residues on ACE2 interacting with the CDR3 domain of 3E8 heavy chain. Although full evaluation of safety in non-human primates is necessary before clinical development of 3E8, we provided a potentially potent and "broad-spectrum" management strategy against all coronaviruses that utilize ACE2 as entry receptors and disclosed an anti-coronavirus epitope on human ACE2.


Subject(s)
Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Antibodies, Monoclonal, Murine-Derived/pharmacology , Antiviral Agents/pharmacology , COVID-19/drug therapy , SARS-CoV-2/immunology , Angiotensin-Converting Enzyme 2/immunology , Animals , Antibodies, Monoclonal, Murine-Derived/immunology , Antiviral Agents/immunology , Chlorocebus aethiops , Disease Models, Animal , HEK293 Cells , Humans , Mice , Mice, Inbred BALB C , Mice, Transgenic , Vero Cells
18.
Front Immunol ; 12: 664619, 2021.
Article in English | MEDLINE | ID: covidwho-1325524

ABSTRACT

Recent studies have highlighted observations regarding re-tested positivity (RP) of SARS-CoV-2 RNA in discharged COVID-19 patients, however, the immune mechanisms underlying SARS-CoV-2 RNA RP in immunocompetent patients remain elusive. Herein, we describe the case of an immunocompetent COVID-19 patient with moderate symptoms who was twice re-tested as positive for SARS-CoV-2 RNA, and the period between first and third viral RNA positivity was 95 days, longer than previously reported (18-25 days). The chest computed tomography findings, plasma anti-SARS-CoV-2 antibody, neutralizing antibodies (NAbs) titer, and whole blood transcriptic characteristics in the viral RNA RP patient and other COVID-19 patients were analyzed. During the SARS-CoV-2 RNA RP period, new lung lesions were observed. The COVID-19 patient with viral RNA RP had delayed seroconversion of anti-spike/receptor-binding domain (RBD) IgA antibody and NAbs and were accompanied with disappearance of the lung lesions. Further experimental data validated that NAbs titer was significantly associated with anti-RBD IgA and IgG, and anti-spike IgG. The RP patient had lower interferon-, T cells- and B cell-related genes expression than non-RP patients with mild-to-moderate symptoms, and displayed lower cytokines and chemokines gene expression than severe patients. Interestingly, the RP patient had low expression of antigen presentation-related genes and low B cell counts which might have contributed to the delayed anti-RBD specific antibody and low CD8+ cell response. Collectively, delayed antigen presentation-related gene expression was found related to delayed adaptive immune response and contributed to the SARS-CoV-2 RNA RP in this described immunocompetent patient.


Subject(s)
COVID-19/immunology , COVID-19/virology , RNA, Viral/isolation & purification , Adaptive Immunity , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , COVID-19/diagnosis , Coronavirus Nucleocapsid Proteins/immunology , Gene Expression Profiling , Humans , Immunity, Innate , Male , Middle Aged , Phosphoproteins/immunology , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification , Seroconversion , Spike Glycoprotein, Coronavirus/immunology
19.
Immunity ; 54(6): 1304-1319.e9, 2021 06 08.
Article in English | MEDLINE | ID: covidwho-1246001

ABSTRACT

Despite mounting evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) engagement with immune cells, most express little, if any, of the canonical receptor of SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2). Here, using a myeloid cell receptor-focused ectopic expression screen, we identified several C-type lectins (DC-SIGN, L-SIGN, LSECtin, ASGR1, and CLEC10A) and Tweety family member 2 (TTYH2) as glycan-dependent binding partners of the SARS-CoV-2 spike. Except for TTYH2, these molecules primarily interacted with spike via regions outside of the receptor-binding domain. Single-cell RNA sequencing analysis of pulmonary cells from individuals with coronavirus disease 2019 (COVID-19) indicated predominant expression of these molecules on myeloid cells. Although these receptors do not support active replication of SARS-CoV-2, their engagement with the virus induced robust proinflammatory responses in myeloid cells that correlated with COVID-19 severity. We also generated a bispecific anti-spike nanobody that not only blocked ACE2-mediated infection but also the myeloid receptor-mediated proinflammatory responses. Our findings suggest that SARS-CoV-2-myeloid receptor interactions promote immune hyperactivation, which represents potential targets for COVID-19 therapy.


Subject(s)
COVID-19/metabolism , COVID-19/virology , Host-Pathogen Interactions , Lectins, C-Type/metabolism , Membrane Proteins/metabolism , Myeloid Cells/immunology , Myeloid Cells/metabolism , Neoplasm Proteins/metabolism , SARS-CoV-2/physiology , Angiotensin-Converting Enzyme 2/metabolism , Binding Sites , COVID-19/genetics , Cell Line , Cytokines , Gene Expression Regulation , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Inflammation Mediators/metabolism , Lectins, C-Type/chemistry , Membrane Proteins/chemistry , Models, Molecular , Neoplasm Proteins/chemistry , Protein Binding , Protein Conformation , Single-Domain Antibodies/immunology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , Structure-Activity Relationship
20.
Nurs Open ; 8(6): 3527-3537, 2021 11.
Article in English | MEDLINE | ID: covidwho-1220262

ABSTRACT

AIM: To investigate the influencing factors in professional identity of undergraduate nursing students after the outbreak of COVID-19. DESIGN: Cross-sectional study. METHODS: The study covered 2,999 nursing students in six undergraduate nursing schools. Several self-report questionnaires were used to collect the general information, psychological stress, coping styles and professional identity of the undergraduate nursing students. RESULTS: The overall average score of the professional identity of nursing students (3.67 ± 0.51) has increased significantly after the outbreak of COVID-19. The professional identity of the undergraduate nursing students was negatively correlated with psychological stress (r = -0.23, p < .001), expectation (r = -0.12, p < .001) and avoidance (r = -0.16, p < .001), but was positively correlated with solving problems (r = 0.18, p < .001) and seeking support (r = 0.12, p < .001). Academic performance, positions, grades, reasons for choosing a nursing profession, parents or relatives engaged in nursing work and the risk degree of residence were the factors influencing the professional identity score of undergraduate nursing students' (p < .001).


Subject(s)
COVID-19 , Education, Nursing, Baccalaureate , Students, Nursing , Adaptation, Psychological , Cross-Sectional Studies , Disease Outbreaks , Humans , SARS-CoV-2 , Stress, Psychological/epidemiology
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