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1.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-334259

ABSTRACT

We found four striking differences in the COVID-19 case fatality rate (CFR) or the ratio of symptomatic COVID-19 cases versus asymptomatic infections. These striking differences all suggest that the risk for China to move away from its zero-COVID policy shall depend on China’s control measures. The CFR of COVID-19 in China can remain less than one tenth of influenza, namely that COVID-19 can be “tiny influenza”in China, if COVID-19 cases shall be well isolated in well disinfected environments (e.g., staying at well-disinfected home) with good maintenance treatment, to minimize their co-infections and maintain their body functions. Otherwise, the CFR of COVID-19 in China can be several times higher than influenza, namely that COVID-19 can be “giant influenza”in China. This analysis is also important to mitigate COVID-19 worldwide.

2.
J Med Virol ; 2022 Apr 12.
Article in English | MEDLINE | ID: covidwho-1782626

ABSTRACT

The Middle East Respiratory Syndrome Coronavirus (MERS-CoV), along with the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), and the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), are three emerging coronaviruses with significant public health implications in the twenty-first century. SARS-CoV-2, in particular, has caused an unprecedented global pandemic, spreading to over 200 countries. As of the manuscript submission date, more than 450 million people were infected with SARS-CoV-2, with near 6 million of those infected dying. This article is protected by copyright. All rights reserved.

3.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-315890

ABSTRACT

Background: Early diagnostic indicators and the identification of possible progression to severe or critical COVID-19 in children are unknown. To investigate the immune characteristics of early SARS-CoV-2 infection in children and possible key prognostic factors for early identification of critical COVID-19, a retrospective study including 121 children with COVID-19 was conducted. Peripheral blood lymphocyte subset counts, T cell-derived cytokine concentrations, inflammatory factor concentrations, and routine blood counts were analyzed statistically at the initial presentation. Results: The T lymphocyte subset and natural killer cell counts decreased with increasing disease severity. Group III (critical cases) had a higher Th/Tc ratio than groups I and II (common and severe cases);group I had a higher B cell count than groups II and III. IL-6, IL-10, IFN-γ, SAA, and procalcitonin levels increased with disease severity. Hemoglobin concentration, and RBC and eosinophil counts decreased with disease severity. Groups II and III had significantly lower lymphocyte counts than group I. T, Th, Tc, IL-6, IL-10, RBC, and hemoglobin had relatively high contribution and area under the curve values. Conclusions: Decreased T, Th, Tc, RBC, hemoglobin and increased IL-6 and IL-10 in early SARS-CoV-2 infection in children are valuable indices for early diagnosis of disease severity. The significantly reduced Th and Tc cells and significantly increased IL-6, IL-10, ferritin, procalcitonin, and SAA at this stage in children with critical COVID-19 may be closely associated with the systemic cytokine storm caused by immune dysregulation.

4.
Infect Dis Poverty ; 11(1): 15, 2022 Feb 02.
Article in English | MEDLINE | ID: covidwho-1666677

ABSTRACT

BACKGROUND: COVID-19 pandemic continues, clarifying signatures in clinical characters and antibody responses between severe and non-severe COVID-19 cases would benefit the prognosis and treatment. METHODS: In this study, 119 serum samples from 37 severe or non-severe COVID-19 patients from the First People's Hospital of Yueyang were collected between January 25 and February 18 2020. The clinical features, antibody responses targeting SARS-CoV-2 spike protein (S) and its different domains, SARS-CoV-2-specific Ig isotypes, IgG subclasses, ACE2 competitive antibodies, binding titers with FcγIIa and FcγIIb receptors, and 14 cytokines were comprehensively investigated. The differences between severe and non-severe groups were analyzed using Mann-Whitney U test or Fisher's exact test. RESULTS: Severe group including 9 patients represented lower lymphocyte count, higher neutrophil count, higher level of LDH, total bile acid (TBA) (P < 1 × 10-4), r-glutaminase (P = 0.011), adenosine deaminase (P < 1 × 10-4), procalcitonin (P = 0.004), C-reactive protein (P < 1 × 10-4) and D-dimer (P = 0.049) compared to non-severe group (28 patients). Significantly, higher-level Igs targeting S, different S domains (RBD, RBM, NTD, and CTD), FcγRIIa and FcγRIIb binding capability were observed in a severe group than that of a non-severe group, of which IgG1 and IgG3 were the main IgG subclasses. RBD-IgG were strongly correlated with S-IgG both in severe and non-severe group. Additionally, CTD-IgG was strongly correlated with S-IgG in a non-severe group. Positive RBD-ACE2 binding inhibition was strongly associated with high titers of antibody (S-IgG1, S-IgG3, NTD-IgG, RBD-IgA, NTD-IgA, and CTD-IgA) especially RBD-IgG and CTD-IgG in the severe group, while in the non-severe group, S-IgG3, RBD-IgG, NTD-IgG, and NTD-IgM were correlated with ACE2 blocking rate. S-IgG1, NTD-IgM and S-IgM were negatively associated with illness day in a severe group, while S-IgG3, RBD-IgA, CTD-IgA in the severe group (r = 0.363, P = 0.011) and S-IgG1, NTD-IgA, CTD-IgA in the non-severe group were positively associated with illness day. Moreover, GRO-α, IL-6, IL-8, IP-10, MCP-1, MCP-3, MIG, and BAFF were also significantly elevated in the severe group. CONCLUSION: Antibody detection provides important clinical information in the COVID-19 process. The different signatures in Ig isotypes, IgG subclasses, antibody specificity between the COVID-19 severe and non-severe group will contribute to future therapeutic and preventive measures development.


Subject(s)
Antibodies, Viral/blood , COVID-19 , COVID-19/diagnosis , COVID-19/immunology , Humans , Immunoglobulin G/blood , Immunoglobulin Isotypes/blood , Pandemics , SARS-CoV-2 , Severity of Illness Index , Spike Glycoprotein, Coronavirus/immunology
5.
Anal Chem ; 94(3): 1626-1636, 2022 01 25.
Article in English | MEDLINE | ID: covidwho-1621191

ABSTRACT

(Mi)RNAs are important biomarkers for cancers diagnosis and pandemic diseases, which require fast, ultrasensitive, and economical detection strategies to quantitatively detect exact (mi)RNAs expression levels. The novel coronavirus disease (SARS-CoV-2) has been breaking out globally, and RNA detection is the most effective way to identify the SARS-CoV-2 virus. Here, we developed an ultrasensitive poly-l-lysine (PLL)-functionalized graphene field-effect transistor (PGFET) biosensor for breast cancer miRNAs and viral RNA detection. PLL is functionalized on the channel surface of GFET to immobilize DNA probes by the electrostatic force. The results show that PGFET biosensors can achieve a (mi)RNA detection range of five orders with a detection limit of 1 fM and an entire detection time within 20 min using 2 µL of human serum and throat swab samples, which exhibits more than 113% enhancement in terms of sensitivity compared to that of GFET biosensors. The performance enhancement mechanisms of PGFET biosensors were comprehensively studied based on an electrical biosensor theoretical model and experimental results. In addition, the PGFET biosensor was applied for the breast cancer miRNA detection in actual serum samples and SARS-CoV-2 RNA detection in throat swab samples, providing a promising approach for rapid cancer diagnosis and virus screening.


Subject(s)
Biosensing Techniques , Breast Neoplasms , COVID-19 , Graphite , MicroRNAs , Breast Neoplasms/diagnosis , Breast Neoplasms/genetics , COVID-19/diagnosis , Female , Humans , Polylysine , RNA, Viral/genetics , SARS-CoV-2
6.
iScience ; 24(12): 103426, 2021 Dec 17.
Article in English | MEDLINE | ID: covidwho-1509907

ABSTRACT

Glycosylation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein mediates viral entry and immune escape. While glycan site is determined by viral genetic code, glycosylation is completely dependent on host cell post-translational modification. Here, by producing SARS-CoV-2 virions from various host cell lines, viruses of different origins with diverse spike protein glycan patterns were revealed. Binding affinities to C-type lectin receptors (CLRs) DC&L-SIGN differed in the different glycan pattern virions. Although none of the CLRs supported viral productive infection, viral trans&cis-infection mediated by the CLRs were substantially changed among the different virions. Specifically, trans&cis-infection of virions with a high-mannose structure (Man5GlcNAc2) at the N1098 glycan site of the spike postfusion trimer were markedly enhanced. Considering L-SIGN co-expression with ACE2 on respiratory tract cells, our work underlines viral epigenetic glycosylation in authentic viral infection and highlights the attachment co-receptor role of DC&L-SIGN in SARS-CoV-2 infection and prevention.

7.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-292320

ABSTRACT

Clinical and Immune response characteristics of COVID-19 between severe and non-severe patients have not been fully clarified. In this study, clinical features, antibody responses targeting SARS-CoV-2 spike protein (S) and its different domains, Ig isotypes and IgG subtypes, ACE2 competitive antibodies, binding titers with FcγIIa and FcγIIb receptors, and 14 cytokines were investigated in 119 serum samples from 37 PCR-confirmed COVID-19 patients. Severe group including 9 patients represented lower lymphocyte count, higher neutrophil count, higher level of LDH, total bile acid (TBA) ( P <1×10 -4 ), r-glutaminase ( P =0.011), adenosine deaminase ( P <1×10 -4 ), procalcitonin (P=0.004), C-reactive protein ( P <1×10 -4 ) and D-dimer (P=0.049) compared to non-severe group (28 patients). Significantly, higher-level antibody targeting S (IgA, IgM, and IgG), different S domains specificity (RBD, RBM, NTD, and CTD), FcγIIa and FcγIIb binding capability were observed in severe group than that of non-severe group, of which IgG1 and IgG3 were the main IgG subclasses. RBD-IgG were strongly correlated with S-IgG both in severe group and non-severe group. Additionally, CTD-IgG were strongly correlated with S-IgG in non-severe group. Positive RBD-ACE2 binding inhibition was strongly associated with high titers of antibody (S-IgG1, S-IgG3, NTD-IgG) especially RBD-IgG and CTD-IgG in severe group, while in non-severe group, S-IgG3, RBD-IgG and NTD-IgG titer correlated with ACE2 blocking rate. S-IgG1 was negatively associated with illness days in severe group (r=- 0.434, P=0.002), while S-IgG3 in severe group (r=0.363, P=0.011) and S-IgG1 (r=0.417, P=3×10-4) in non-severe group was positively associated with days after symptom onset. Moreover, GRO-α, IL-6, IL-8, IP-10, MCP-1, MCP-3, MIG, and BAFF were also significantly elevated in severe group. Overall, the results indicated different signatures in clinical and immune responses between the COVID-19 severe group and non-severe group, which will be markedly contributed to future therapeutic and preventive measures development.

8.
J Immunol ; 206(11): 2527-2535, 2021 06 01.
Article in English | MEDLINE | ID: covidwho-1227097

ABSTRACT

The T cell response is an important detection index in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine development. The present study was undertaken to determine the T cell epitopes in the spike (S) protein of SARS-CoV-2 that dominate the T cell responses in SARS-CoV-2-infected patients. PBMCs from rhesus macaques vaccinated with a DNA vaccine encoding the full-length S protein were isolated, and an ELISPOT assay was used to identify the recognized T cell epitopes among a total of 158 18-mer and 10-aa-overlapping peptides spanning the full-length S protein. Six multipeptide-based epitopes located in the S1 region, with four of the six located in the receptor-binding domain, were defined as the most frequently recognized epitopes in macaques. The conservation of the epitopes across species was also verified, and peptide mixtures for T cell response detection were established. Six newly defined T cell epitopes were found in the current study, which may provide a novel potential target for T cell response detection and the diagnosis and vaccine design of SARS-CoV-2 based on multipeptide subunit-based epitopes.


Subject(s)
Epitopes, T-Lymphocyte/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Animals , Macaca mulatta
9.
BMC Pediatr ; 21(1): 181, 2021 04 17.
Article in English | MEDLINE | ID: covidwho-1190064

ABSTRACT

BACKGROUND: Early diagnostic indicators and the identification of possible progression to severe or critical COVID-19 in children are unknown. To investigate the immune characteristics of early SARS-CoV-2 infection in children and possible key prognostic factors for early identification of critical COVID-19, a retrospective study including 121 children with COVID-19 was conducted. Peripheral blood lymphocyte subset counts, T cell-derived cytokine concentrations, inflammatory factor concentrations, and routine blood counts were analyzed statistically at the initial presentation. RESULTS: The T lymphocyte subset and natural killer cell counts decreased with increasing disease severity. Group III (critical cases) had a higher Th/Tc ratio than groups I and II (common and severe cases); group I had a higher B cell count than groups II and III. IL-6, IL-10, IFN-γ, SAA, and procalcitonin levels increased with increasing disease severity. Hemoglobin concentration, and RBC and eosinophil counts decreased with increasing disease severity. Groups II and III had significantly lower lymphocyte counts than group I. T, Th, Tc, IL-6, IL-10, RBC, and hemoglobin had relatively high contribution and area under the curve values. CONCLUSIONS: Decreased T, Th, Tc, RBC, hemoglobin and increased IL-6 and IL-10 in early SARS-CoV-2 infection in children are valuable indices for early diagnosis of severe disease. The significantly reduced Th and Tc cells and significantly increased IL-6, IL-10, ferritin, procalcitonin, and SAA at this stage in children with critical COVID-19 may be closely associated with the systemic cytokine storm caused by immune dysregulation.


Subject(s)
COVID-19/diagnosis , Systemic Inflammatory Response Syndrome/diagnosis , Adolescent , B-Lymphocytes/cytology , Child , Child, Preschool , Cytokine Release Syndrome/virology , Cytokines/blood , Female , Humans , Immunity , Infant , Killer Cells, Natural/cytology , Lymphocyte Count , Male , Prognosis , Retrospective Studies , Severity of Illness Index , T-Lymphocyte Subsets/cytology
10.
J Clin Gastroenterol ; 55(1): 67-76, 2021 01.
Article in English | MEDLINE | ID: covidwho-1140031

ABSTRACT

BACKGROUND: The worldwide outbreak of COVID-19 infected millions of people. Some patients had gastrointestinal (GI) symptoms, abnormal liver function, digestive system disease and liver disease. AIM: To investigate the prevalence of GI symptoms, abnormal liver function, digestive system disease and liver disease in patients with COVID-19 by a systematic review and meta-analysis. METHODS: We searched PubMed, Ovid Embase, Medline, and 2 Chinese databases. Primary outcomes were the prevalence of GI symptoms, abnormal liver function, digestive system disease, and liver disease. Different studies were included in different subset analysis. These outcomes were estimated with proportions, odds ratio, 95% confidence interval (CI) and P-value by Stata SE 15.1. RESULTS: Thirty-one studies involving 4682 patients were included. The most significant GI symptoms were diarrhea (0.08, 95% CI: 0.06-0.11) and anorexia (0.17, 95% CI: 0.06-0.27). The most significant abnormal liver function was increased alanine aminotransferase (ALT) (0.25, 95% CI: 0.16-0.33). A total of 5% of the patients had digestive system disease (95% CI: 0.02-0.08). A total of 3% of the patients had liver disease (95% CI: 0.02-0.05). The prevalence of nausea and vomiting, diarrhea, abnormal liver function, digestive system disease, and liver disease was higher in Wuhan group. The prevalence of diarrhea was higher in non-China group. Patients in severe/intensive care unit group were more likely to have diarrhea, anorexia, abdominal pain increased aspartate aminotransferase, and increased ALT. CONCLUSION: The most significant GI symptoms were anorexia and diarrhea. The most significant abnormal liver function was increased ALT. Severe patients were more likely to have GI symptoms and abnormal liver function.


Subject(s)
COVID-19/complications , Gastrointestinal Diseases/epidemiology , Gastrointestinal Diseases/virology , Liver Diseases/epidemiology , Liver Diseases/virology , COVID-19/diagnosis , COVID-19 Testing , Gastrointestinal Diseases/diagnosis , Global Health , Humans , Liver Diseases/diagnosis , Prevalence
11.
Burns Trauma ; 8: tkaa048, 2020.
Article in English | MEDLINE | ID: covidwho-1109169

ABSTRACT

There is little research that focuses on the relationship between the gut, metabolism, nutritional support and COVID-19. As a group of Chinese physicians, nutritionists and scientists working on the frontline treating COVID-19 patients, we aim to integrate our experiences and the current clinical evidence to address this pressing issue in this article. Based on our clinical observations and available evidence, we recommend the following practice. Firstly, the Nutritional Risk Screening 2002 tool should be used routinely and periodically; for patients with a score ≥3, oral nutritional supplements should be given immediately. Secondly, for patients receiving the antiviral agents lopinavir/ritonavir, gastrointestinal side effects should be monitored for and timely intervention provided. Thirdly, for feeding, the enteral route should be the first choice. In patients undergoing mechanical ventilation, establishing a jejunal route as early as possible can guarantee the feeding target being achieved if gastric dilatation occurs. Fourthly, we suggest a permissive underfeeding strategy for severe/critical patients admitted to the intensive care unit during the first week of admission, with the energy target no more than 20 kcal/kg/day (for those on mechanical ventilation, this target may be lowered to 10-15 kcal/kg/day) and the protein target around 1.0-1.2 g/kg/day. If the inflammatory condition is significantly alleviated, the energy target may be gradually increased to 25-30 kcal/kg/day and the protein target to 1.2-1.5 g/kg/day. Fifthly, supplemental parenteral nutrition should be used with caution. Lastly, omega-3 fatty acids may be used as immunoregulators, intravenous administration of omega-3 fatty emulsion (10 g/day) at an early stage may help to reduce the inflammatory reaction.

12.
J Biol Chem ; 296: 100435, 2021.
Article in English | MEDLINE | ID: covidwho-1087033

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic represents a global threat, and the interaction between the virus and angiotensin-converting enzyme 2 (ACE2), the primary entry receptor for SARS-CoV-2, is a key determinant of the range of hosts that can be infected by the virus. However, the mechanisms underpinning ACE2-mediated viral entry across species remains unclear. Using infection assay, we evaluated SARS-CoV-2 entry mediated by ACE2 of 11 different animal species. We discovered that ACE2 of Rhinolophus sinicus (Chinese rufous horseshoe bat), Felis catus (domestic cat), Canis lupus familiaris (dog), Sus scrofa (wild pig), Capra hircus (goat), and Manis javanica (Malayan pangolin) facilitated SARS-CoV-2 entry into nonsusceptible cells. Moreover, ACE2 of the pangolin also mediated SARS-CoV-2 entry, adding credence to the hypothesis that SARS-CoV-2 may have originated from pangolins. However, the ACE2 proteins of Rhinolophus ferrumequinum (greater horseshoe bat), Gallus gallus (red junglefowl), Notechis scutatus (mainland tiger snake), or Mus musculus (house mouse) did not facilitate SARS-CoV-2 entry. In addition, a natural isoform of the ACE2 protein of Macaca mulatta (rhesus monkey) with the Y217N mutation was resistant to SARS-CoV-2 infection, highlighting the possible impact of this ACE2 mutation on SARS-CoV-2 studies in rhesus monkeys. We further demonstrated that the Y217 residue of ACE2 is a critical determinant for the ability of ACE2 to mediate SARS-CoV-2 entry. Overall, these results clarify that SARS-CoV-2 can use the ACE2 receptors of multiple animal species and show that tracking the natural reservoirs and intermediate hosts of SARS-CoV-2 is complex.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/epidemiology , COVID-19/transmission , Pandemics , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/genetics , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/immunology , Animals , COVID-19/diagnosis , COVID-19/immunology , Cats , Chickens/virology , Chiroptera/virology , Dogs , Elapidae/virology , Eutheria/virology , Gene Expression , Goats/virology , HEK293 Cells , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Immunity, Innate , Macaca mulatta/virology , Mice , Models, Molecular , Mutation , Protein Binding , Protein Structure, Secondary , Recombinant Proteins/genetics , Recombinant Proteins/immunology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Species Specificity , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Swine/virology , Virus Internalization
13.
SSRN; 2020.
Preprint | SSRN | ID: ppcovidwho-5890

ABSTRACT

Background: Our study is to test the association between front-line clinical workers' fatigue and depression and anxiety during the COVID-19 epidemic. brbr

14.
J Dent Sci ; 16(1): 493-500, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-997119

ABSTRACT

Coronavirus disease (COVID-19) pandemic has become a significant global public health concern. Since the announcement of the Public Health Emergency of International Concern, many countries have implemented lockdown and restrictive quarantines; therefore, routine dentistry, as well as oral medicine practise, have been suspended in several countries. However, urgent oral cares and emergencies are still operated and delivered by on-call dental practitioners. The objective of this study was to investigate the management of oral medicine emergency during a viral pandemic such as COVID-19. During the lockdown period, digital technologies, such as video conferencing with Zoom, Google Meeting or WhatsApp, are useful and efficient tools that oral medicine practitioners could consider to use for patient triage, managing emergencies, reassure, and follow patients remotely. Oral medicine emergencies can be carefully evaluated and triaged via video conferencing and sometimes phone contact, to avoid life-threatening risks while realising the limitations by both patient and clinician.

15.
Hum Vaccin Immunother ; 17(4): 1097-1108, 2021 04 03.
Article in English | MEDLINE | ID: covidwho-917625

ABSTRACT

T cell immunity, such as CD4 and/or CD8 T cell responses, plays a vital role in controlling the virus infection and pathological damage. Several studies have reported SARS-CoV-2 proteins could serve as ideal vaccine candidates against SARS-CoV-2 infection by activating the T cell responses. In the current study, based on the SARS-CoV-2 sequence and distribution of host human leukocyte antigen (HLA), we predicted the possible epitopes for the vaccine against SARS-CoV-2 infections. Firstly, the current study retrieved the SARS-CoV-2 S and N protein sequences from the NCBI Database. Then, using the Immune Epitope Database Analysis Resource, we predicted the CTL epitopes of the SARS-CoV-2 S and N proteins according to worldwide frequency distributions of HLA-A, -B, and -C alleles (>1%). Our results predicted 90 and 106 epitopes of N and S proteins, respectively. Epitope cluster analysis showed 16 and 34 respective clusters of SARS-CoV-2 N and S proteins, which covered 95.91% and 96.14% of the global population, respectively. After epitope conservancy analysis, 8 N protein epitopes and 6 S protein epitopes showed conservancy within two SARS-CoV-2 types. Of these 14 epitopes, 13 could cover SARS coronavirus and Bat SARS-like coronavirus. The remaining epitope (KWPWYIWLGF1211-1220) could cover MERS coronavirus. Finally, the 14-epitope combination could vaccinate 89.60% of all individuals worldwide. Our results propose single or combined CTL epitopes predicted in the current study as candidates for vaccines to effectively control SARS-CoV-2 infection and development.


Subject(s)
COVID-19 Vaccines/immunology , Coronavirus Nucleocapsid Proteins/immunology , Epitopes, T-Lymphocyte/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , COVID-19/prevention & control , Epitopes, B-Lymphocyte/immunology , HLA-A Antigens/immunology , HLA-B Antigens/immunology , HLA-C Antigens/immunology , Humans , Immunogenicity, Vaccine/immunology , Phosphoproteins/immunology
16.
Science ; 370(6523): 1473-1479, 2020 12 18.
Article in English | MEDLINE | ID: covidwho-913670

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus enters host cells via an interaction between its Spike protein and the host cell receptor angiotensin-converting enzyme 2 (ACE2). By screening a yeast surface-displayed library of synthetic nanobody sequences, we developed nanobodies that disrupt the interaction between Spike and ACE2. Cryo-electron microscopy (cryo-EM) revealed that one nanobody, Nb6, binds Spike in a fully inactive conformation with its receptor binding domains locked into their inaccessible down state, incapable of binding ACE2. Affinity maturation and structure-guided design of multivalency yielded a trivalent nanobody, mNb6-tri, with femtomolar affinity for Spike and picomolar neutralization of SARS-CoV-2 infection. mNb6-tri retains function after aerosolization, lyophilization, and heat treatment, which enables aerosol-mediated delivery of this potent neutralizer directly to the airway epithelia.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Single-Domain Antibodies/immunology , Spike Glycoprotein, Coronavirus/immunology , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/immunology , Animals , Antibodies, Neutralizing/chemistry , Antibodies, Viral/chemistry , Antibody Affinity , Chlorocebus aethiops , Cryoelectron Microscopy , Humans , Neutralization Tests , Protein Binding , Protein Stability , Single-Domain Antibodies/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Vero Cells
17.
SSRN; 2020.
Preprint | SSRN | ID: ppcovidwho-1604

ABSTRACT

Background: Our study is to test the association between front-line clinical workers' fatigue and depression and anxiety during the COVID-19 epidemic. brbr

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