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1.
Commun Biol ; 5(1): 262, 2022 03 24.
Article in English | MEDLINE | ID: covidwho-1799550

ABSTRACT

Understanding the underlying molecular mechanisms behind ADE of SARS-CoV-2 is critical for development of safe and effective therapies. Here, we report that two neutralizing mAbs, MW01 and MW05, could enhance the infection of SARS-CoV-2 pseudovirus on FcγRIIB-expressing B cells. X-ray crystal structure determination and S trimer-binding modeling showed that MW01 and MW05 could bind to RBDs in S trimer with both "up" and "down" states. While, the neutralizing mAb MW07, which has no ADE activity only binds to RBD in S trimer with "up" state. Monovalent MW01 and MW05 completely diminished the ADE activity compared with their bivalent counterparts. Moreover, both macropinocytosis and endocytosis are confirmed involving in ADE of SARS-CoV-2 pseudoviral infection. Blocking endosome transportation and lysosome acidification could inhibit the ADE activity mediated by MW05. Together, our results identified a novel ADE mechanism of SARS-CoV-2 pseudovirus in vitro, FcγRIIB-mediated uptake of SARS-CoV-2/mAb complex with bivalent interaction.


Subject(s)
Antibody-Dependent Enhancement , COVID-19 , Antibodies, Viral , Humans , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
2.
Front Cell Infect Microbiol ; 11: 706252, 2021.
Article in English | MEDLINE | ID: covidwho-1405403

ABSTRACT

The pandemic of COVID-19 by SARS-CoV-2 has become a global disaster. However, we still don't know how specific SARS-CoV-2-encoded proteins contribute to viral pathogenicity. We found that SARS-CoV-2-encoded membrane glycoprotein M could induce caspase-dependent apoptosis via interacting with PDK1 and inhibiting the activation of PDK1-PKB/Akt signaling. Our investigation further revealed that SARS-CoV-2-encoded nucleocapsid protein N could specifically enhance the M-induced apoptosis via interacting with both M and PDK1, therefore strengthening M-mediated attenuation of PDK1-PKB/Akt interaction. Furthermore, when the M-N interaction was disrupted via certain rationally designed peptides, the PDK1-PKB/Akt signaling was restored, and the boosting activity of N on the M-triggered apoptosis was abolished. Overall, our findings uncovered a novel mechanism by which SARS-CoV-2-encoded M triggers apoptosis with the assistance of N, which expands our understanding of the two key proteins of SARS-CoV-2 and sheds light on the pathogenicity of this life-threatening virus.


Subject(s)
COVID-19 , SARS-CoV-2 , Apoptosis , Humans , Membrane Glycoproteins , Nucleocapsid Proteins , Spike Glycoprotein, Coronavirus
3.
MAbs ; 13(1): 1953683, 2021.
Article in English | MEDLINE | ID: covidwho-1327301

ABSTRACT

The global pandemic of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in widespread social and economic disruption. Effective interventions are urgently needed for the prevention and treatment of COVID-19. Neutralizing monoclonal antibodies (mAbs) have demonstrated their prophylactic and therapeutic efficacy against SARS-CoV-2, and several have been granted authorization for emergency use. Here, we discover and characterize a fully human cross-reactive mAb, MW06, which binds to both SARS-CoV-2 and SARS-CoV spike receptor-binding domain (RBD) and disrupts their interaction with angiotensin-converting enzyme 2 (ACE2) receptors. Potential neutralization activity of MW06 was observed against both SARS-CoV-2 and SARS-CoV in different assays. The complex structure determination and epitope alignment of SARS-CoV-2 RBD/MW06 revealed that the epitope recognized by MW06 is highly conserved among SARS-related coronavirus strains, indicating the potential broad neutralization activity of MW06. In in vitro assays, no antibody-dependent enhancement (ADE) of SARS-CoV-2 infection was observed for MW06. In addition, MW06 recognizes a different epitope from MW05, which shows high neutralization activity and has been in a Phase 2 clinical trial, supporting the development of the cocktail of MW05 and MW06 to prevent against future escaping variants. MW06 alone and the cocktail show good effects in preventing escape mutations, including a series of variants of concern, B.1.1.7, P.1, B.1.351, and B.1.617.1. These findings suggest that MW06 recognizes a conserved epitope on SARS-CoV-2, which provides insights for the development of a universal antibody-based therapy against SARS-related coronavirus and emerging variant strains, and may be an effective anti-SARS-CoV-2 agent.


Subject(s)
Antibodies, Monoclonal, Humanized/immunology , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , COVID-19/virology , SARS Virus/immunology , SARS-CoV-2/immunology , Amino Acid Sequence , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Neutralizing/chemistry , Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/chemistry , Antibodies, Viral/therapeutic use , Antibody-Dependent Enhancement , COVID-19/drug therapy , COVID-19/therapy , Conserved Sequence , Cross Reactions , Epitopes/chemistry , Epitopes/genetics , Epitopes/immunology , Humans , Models, Molecular , Neutralization Tests , Pandemics , Protein Domains , Protein Interaction Domains and Motifs , SARS Virus/chemistry , SARS Virus/genetics , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology
4.
Clin Transl Sci ; 14(1): 132-136, 2021 01.
Article in English | MEDLINE | ID: covidwho-952459

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly identified pathogen causing the coronavirus disease 2019 (COVID-19) pandemic. Hydroxychloroquine (HCQ), an antimalarial and anti-inflammatory drug, has been shown to inhibit SARS-CoV-2 infection in vitro and tested in clinical studies. However, achievement of lung concentrations predicted to have in vivo antiviral efficacy might not be possible with the currently proposed oral dosing regimens. Further, high cumulative doses of HCQ raise concerns of systemic toxicity, including cardiotoxicity. Here, we describe a preclinical study to investigate the pharmacokinetics (PKs) of a novel formulation of liposomal HCQ administered by intratracheal (IT) instillation in Sprague-Dawley rats. Compared with unformulated HCQ administered intravenously, liposomal HCQ showed higher (~ 30-fold) lung exposure, longer (~ 2.5-fold) half-life in lungs, but lower blood exposure with ~ 20% of peak plasma concentration (Cmax ) and 74% of area under the curve from 0 to 72 hours (AUC0-72 ) and lower heart exposure with 23% of Cmax and 58% of AUC0-24 (normalized for dose). Similar results were observed relative to IT administration of unformulated HCQ. These PKs result in an animal model that demonstrated the proof of concept that inhalable liposomal HCQ may provide clinical benefit and serve as a potential treatment for COVID-19.


Subject(s)
COVID-19/drug therapy , Hydroxychloroquine/administration & dosage , SARS-CoV-2 , Administration, Inhalation , Animals , Female , Hydroxychloroquine/adverse effects , Hydroxychloroquine/pharmacokinetics , Liposomes , Lung/metabolism , Rats , Rats, Sprague-Dawley
5.
J Adv Nurs ; 77(4): 1813-1824, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-938330

ABSTRACT

AIMS: To determine psychological symptoms of patients with mild symptoms of coronavirus disease 2019 in China and to explore the influencing factors. DESIGN: A cross-sectional study. METHODS: A convenience sample of 296 mild coronavirus disease 2019 patients were recruited from a Fangcang hospital in Wuhan, Hubei Province, from 3-5 March, 2020. Participants were assessed using a sociodemographic and clinical characteristics questionnaire, and Symptom Check List 90. The binary logistic regression was utilized to explore the influencing factors of psychological symptoms of patients with mild symptoms of coronavirus disease 2019. RESULTS: In total, 296 of 299 patients with mild symptoms of coronavirus disease 2019 participated in the study (response rate: 99.0%). The findings revealed that 12.8% patients with mild symptoms have mental health problems; the most common psychological symptoms are phobic anxiety (58.4%), paranoid ideation (50.7%) and psychoticism (40.2%). Female patients [OR = 3.587, 95% CI (1.694-7.598)] and those having physical symptoms currently [OR = 2.813, 95% CI (1.210-6.539)] are at higher risk, while those in the middle duration of hospitalization [OR = 0.278, 95% CI (0.121-0.639)] protect against mental-health problems. CONCLUSIONS: The minority of patients with mild symptoms of coronavirus disease 2019 were still suffering from psychological symptoms. Healthcare providers are recommended to pay particular attention to screening these high-risk groups (women, those in the initial stages of hospitalization and those with physical symptoms currently) and implement targeted psychological care as required. IMPACT: This study found that most patients of coronavirus disease 2019 in Fangcang hospital exhibited normal mental health at par with the general Chinese norm and the minority of them were suffering from psychological symptoms. The findings can provide a reference for healthcare providers to screen high-risk psychological symptoms groups and implement targeted psychological intervention for patients with coronavirus disease 2019.


Subject(s)
Anxiety Disorders/etiology , COVID-19/complications , COVID-19/epidemiology , COVID-19/psychology , Depressive Disorder/etiology , Symptom Assessment/psychology , Symptom Assessment/statistics & numerical data , Adult , Aged , Aged, 80 and over , Anxiety Disorders/epidemiology , China/epidemiology , Cross-Sectional Studies , Depressive Disorder/epidemiology , Female , Humans , Male , Middle Aged , Prevalence , Surveys and Questionnaires , Young Adult
6.
Nat Commun ; 11(1): 5752, 2020 11 13.
Article in English | MEDLINE | ID: covidwho-926678

ABSTRACT

Efficacious interventions are urgently needed for the treatment of COVID-19. Here, we report a monoclonal antibody (mAb), MW05, with SARS-CoV-2 neutralizing activity by disrupting the interaction of receptor binding domain (RBD) with angiotensin-converting enzyme 2 (ACE2) receptor. Crosslinking of Fc with FcγRIIB mediates antibody-dependent enhancement (ADE) activity by MW05. This activity is eliminated by introducing the LALA mutation to the Fc region (MW05/LALA). Potent prophylactic and therapeutic effects against SARS-CoV-2 are observed in rhesus monkeys. A single dose of MW05/LALA blocks infection of SARS-CoV-2 in prophylactic treatment and clears SARS-CoV-2 in three days in a therapeutic treatment setting. These results pave the way for the development of MW05/LALA as an antiviral strategy for COVID-19.


Subject(s)
Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/immunology , Antiviral Agents/pharmacology , Betacoronavirus/immunology , Coronavirus Infections/therapy , Pneumonia, Viral/therapy , Spike Glycoprotein, Coronavirus/immunology , Angiotensin-Converting Enzyme 2 , Animals , Antibodies, Viral/immunology , COVID-19 , Cell Line , Chlorocebus aethiops , Coronavirus Infections/prevention & control , Female , HEK293 Cells , Humans , Macaca mulatta , Male , Pandemics/prevention & control , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/prevention & control , Receptors, IgG/genetics , Receptors, IgG/immunology , Receptors, Virus/metabolism , SARS-CoV-2 , Vero Cells , Virus Attachment
8.
SSRN; 2020.
Preprint | SSRN | ID: ppcovidwho-740

ABSTRACT

Importance: An ongoing outbreak of COVID-19 has exhibited significant threats around the world. We found a significant decrease of T lymphocyte subsets and an i

11.
Lancet Digit Health ; 2(6): e323-e330, 2020 06.
Article in English | MEDLINE | ID: covidwho-260619

ABSTRACT

Background: The outbreak of COVID-19 has led to international concern. We aimed to establish an effective screening strategy in Shanghai, China, to aid early identification of patients with COVID-19. Methods: We did a multicentre, observational cohort study in fever clinics of 25 hospitals in 16 districts of Shanghai. All patients visiting the clinics within the study period were included. A strategy for COVID-19 screening was presented and then suspected cases were monitored and analysed until they were confirmed as cases or excluded. Logistic regression was used to determine the risk factors of COVID-19. Findings: We enrolled patients visiting fever clinics from Jan 17 to Feb 16, 2020. Among 53 617 patients visiting fever clinics, 1004 (1·9%) were considered as suspected cases, with 188 (0·4% of all patients, 18·7% of suspected cases) eventually diagnosed as confirmed cases. 154 patients with missing data were excluded from the analysis. Exposure history (odds ratio [OR] 4·16, 95% CI 2·74-6·33; p<0·0001), fatigue (OR 1·56, 1·01-2·41; p=0·043), white blood cell count less than 4 × 109 per L (OR 2·44, 1·28-4·64; p=0·0066), lymphocyte count less than 0·8 × 109 per L (OR 1·82, 1·00-3·31; p=0·049), ground glass opacity (OR 1·95, 1·32-2·89; p=0·0009), and having both lungs affected (OR 1·54, 1·04-2·28; p=0·032) were independent risk factors for confirmed COVID-19. Interpretation: The screening strategy was effective for confirming or excluding COVID-19 during the spread of this contagious disease. Relevant independent risk factors identified in this study might be helpful for early recognition of the disease. Funding: National Natural Science Foundation of China.


Subject(s)
COVID-19/diagnosis , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , COVID-19/epidemiology , COVID-19/etiology , COVID-19/pathology , Child , Child, Preschool , China/epidemiology , Female , Fever/etiology , Humans , Infant , Infant, Newborn , Leukocyte Count , Lung/pathology , Male , Middle Aged , Multivariate Analysis , Risk Factors , Young Adult
12.
J Infect ; 81(1): e51-e60, 2020 07.
Article in English | MEDLINE | ID: covidwho-71722

ABSTRACT

IMPORTANCE: An ongoing outbreak of COVID-19 has exhibited significant threats around the world. We found a significant decrease of T lymphocyte subsets and an increase of inflammatory cytokines of hospitalized patients with COVID-19 in clinical practice. METHODS: We conducted a retrospective, single-center observational study of in-hospital adult patients with confirmed COVID-19 in Hubei Provincial Hospital of traditional Chinese and Western medicine (Wuhan, China) by Mar 1, 2020. Demographic, clinical, laboratory information, especially T lymphocyte subsets and inflammatory cytokines were reported. For patients who died or discharge from hospital, the associations of T lymphocyte subsets on admission were evaluated by univariate logistic regression with odds ratios (ORs) and 95% confidence intervals (CIs), warning values to predict in-hospital death were assessed by Receiver Operator Characteristic (ROC) curves. RESULTS: A total of 187 patients were enrolled in our study from Dec 26, 2019 to Mar 1, 2020, of whom 145 were survivors (discharge = 117) or non-survivors (in-hospital death ==28). All patients exhibited a significant drop of T lymphocyte subsets counts with remarkably increasing concentrations of SAA, CRP, IL-6, and IL-10 compared to normal values. The median concentrations of SAA and CRP in critically-ill patients were nearly 4- and 10-fold than those of mild-ill patients, respectively. As the severity of COVID-19 getting worse, the counts of T lymphocyte drop lower.28 patients died in hospital, the median lymphocyte, CD3+ T-cell, CD4+ T-cell, CD8+ T-cell and B-cell were significantly lower than other patients. Lower counts (/uL) of T lymphocyte subsets lymphocyte (<500), CD3+T-cell (<200), CD4+ T-cell (<100), CD8+ T-cell (<100) and B-cell (<50) were associated with higher risks of in-hospital death of CIVID-19. The warning values to predict in-hospital death of lymphocyte, CD3+ T-cell, CD4+ T-cell, CD8+ T-cell, and B-cell were 559, 235, 104, 85 and 82, respectively. CONCLUSION: We find a significant decrease of T lymphocyte subset is positively correlated with in-hospital death and severity of illness. The decreased levels of T lymphocyte subsets reported in our study were similar with SARS but not common among other virus infection, which may be possible biomarkers for early diagnosis of COVID-19. Our findings may shed light on early warning of high risks of mortality and help early intervention and treatment of COVID-19.


Subject(s)
Betacoronavirus , Coronavirus Infections/epidemiology , Coronavirus Infections/immunology , Immunity, Cellular , Pneumonia, Viral/epidemiology , Pneumonia, Viral/immunology , Adult , Aged , COVID-19 , China/epidemiology , Female , Humans , Lymphocyte Count , Male , Middle Aged , Pandemics , Retrospective Studies , SARS-CoV-2 , T-Lymphocyte Subsets
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