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1.
Frontiers in public health ; 10, 2022.
Article in English | EuropePMC | ID: covidwho-1876940

ABSTRACT

Motivation Patients with novel coronavirus disease 2019 (COVID-19) worsen into critical illness suddenly is a matter of great concern. Early identification and effective triaging of patients with a high risk of developing critical illness COVID-19 upon admission can aid in improving patient care, increasing the cure rate, and mitigating the burden on the medical care system. This study proposed and extended classical least absolute shrinkage and selection operator (LASSO) logistic regression to objectively identify clinical determination and risk factors for the early identification of patients at high risk of progression to critical illness at the time of hospital admission. Methods In this retrospective multicenter study, data of 1,929 patients with COVID-19 were assessed. The association between laboratory characteristics measured at admission and critical illness was screened with logistic regression. LASSO logistic regression was utilized to construct predictive models for estimating the risk that a patient with COVID-19 will develop a critical illness. Results The development cohort consisted of 1,363 patients with COVID-19 with 133 (9.7%) patients developing the critical illness. Univariate logistic regression analysis revealed 28 variables were prognosis factors for critical illness COVID-19 (p < 0.05). Elevated CK-MB, neutrophils, PCT, α-HBDH, D-dimer, LDH, glucose, PT, APTT, RDW (SD and CV), fibrinogen, and AST were predictors for the early identification of patients at high risk of progression to critical illness. Lymphopenia, a low rate of basophils, eosinophils, thrombopenia, red blood cell, hematocrit, hemoglobin concentration, blood platelet count, and decreased levels of K, Na, albumin, albumin to globulin ratio, and uric acid were clinical determinations associated with the development of critical illness at the time of hospital admission. The risk score accurately predicted critical illness in the development cohort [area under the curve (AUC) = 0.83, 95% CI: 0.78–0.86], also in the external validation cohort (n = 566, AUC = 0.84). Conclusion A risk prediction model based on laboratory findings of patients with COVID-19 was developed for the early identification of patients at high risk of progression to critical illness. This cohort study identified 28 indicators associated with critical illness of patients with COVID-19. The risk model might contribute to the treatment of critical illness disease as early as possible and allow for optimized use of medical resources.

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.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-324160

ABSTRACT

The unprecedented coronavirus disease 2019 (COVID-19) epidemic has created a worldwide public health emergency, and there is an urgent need to develop an effective vaccine to control this severe infectious disease. Here, we found that a single vaccination with a replication-defective human type 5 adenovirus encoding the SARS-CoV-2 spike protein (Ad5-nCoV) protected mice completely against SARS-CoV-2 infection in the upper and lower respiratory tracts. Additionally, a single vaccination with Ad5-nCoV protected ferrets from SARS-CoV-2 infection in the upper respiratory tract. This study suggested that a combination of intramuscular and mucosal vaccination maybe provide a desirable protective efficacy and different Ad5-nCoV delivery modes are worth further investigation in human clinical trials.

4.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-315719

ABSTRACT

Background: The World Health Organization (WHO) recommends using corticosteroids in patients with severe coronavirus disease 2019 (COVID-19) and acute respiratory distress syndrome (ARDS), and a large randomized controlled clinical trial in the UK found that dexamethasone was effective in reducing the number of deaths in patients with severe COVID-19. Case presentation: Herein, we described a case of COVID-19 with the clinical characteristics of the mild-symptomatic stage deteriorating to a critically ill state, who showed dramatic improvement with corticosteroids in the early stage of worsening of COVID-19 pneumonia. Discussion: This article further discusses the most suitable timing and dosage of corticosteroid to maximize its effect during the worsening of COVID-19 pneumonia.Learning points:• One of the main pathophysiological hypotheses for severe COVID-19 pneumonia is related to cytokine storm and viral load.• The clinical factors should be considered as the initial sign of a cytokine storm, and corticosteroid therapy may be useful in these patients.

5.
Nat Metab ; 4(1): 29-43, 2022 01.
Article in English | MEDLINE | ID: covidwho-1612214

ABSTRACT

Severe cases of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are associated with elevated blood glucose levels and metabolic complications. However, the molecular mechanisms for how SARS-CoV-2 infection alters glycometabolic control are incompletely understood. Here, we connect the circulating protein GP73 with enhanced hepatic gluconeogenesis during SARS-CoV-2 infection. We first demonstrate that GP73 secretion is induced in multiple tissues upon fasting and that GP73 stimulates hepatic gluconeogenesis through the cAMP/PKA signaling pathway. We further show that GP73 secretion is increased in cultured cells infected with SARS-CoV-2, after overexpression of SARS-CoV-2 nucleocapsid and spike proteins and in lungs and livers of mice infected with a mouse-adapted SARS-CoV-2 strain. GP73 blockade with an antibody inhibits excessive glucogenesis stimulated by SARS-CoV-2 in vitro and lowers elevated fasting blood glucose levels in infected mice. In patients with COVID-19, plasma GP73 levels are elevated and positively correlate with blood glucose levels. Our data suggest that GP73 is a glucogenic hormone that likely contributes to SARS-CoV-2-induced abnormalities in systemic glucose metabolism.


Subject(s)
COVID-19/complications , COVID-19/virology , Glucose/metabolism , Hyperglycemia/etiology , Hyperglycemia/metabolism , Membrane Proteins/metabolism , SARS-CoV-2 , Animals , Biomarkers , Cyclic AMP-Dependent Protein Kinases/metabolism , Diet, High-Fat , Disease Models, Animal , Fasting , Gene Expression , Gluconeogenesis/drug effects , Gluconeogenesis/genetics , Host-Pathogen Interactions , Humans , Hyperglycemia/blood , Liver/metabolism , Liver/pathology , Membrane Proteins/antagonists & inhibitors , Membrane Proteins/blood , Membrane Proteins/genetics , Mice , Mice, Knockout , Organ Specificity/genetics
6.
Infect Drug Resist ; 14: 2667-2674, 2021.
Article in English | MEDLINE | ID: covidwho-1319550

ABSTRACT

BACKGROUND: The World Health Organization (WHO) strongly suggests using corticosteroids in patients with severe coronavirus disease 2019 (COVID-19). Similarly, a large randomized controlled clinical trial (RCT) in the UK found that dexamethasone effectively reduced the mortality rate in severe COVID-19 patients. However, the safety profile of corticosteroids has been a controversial area of study. CASE DESCRIPTION: A case of a COVID-19 patient is described and the clinical characteristics are observed as the mildly symptomatic patient progresses into a critically ill patient and during their dramatic improvement with corticosteroid therapy in the early stage of the deterioration process with COVID-19 pneumonia. CONCLUSION: The most suitable timing and dosage for the use of corticosteroids to maximize its effect during the worsening of COVID-19 pneumonia are discussed. One of the main pathophysiological hypotheses for severe COVID-19 patients is related to cytokine storm and virus load, which can be effectively treated with corticosteroid therapy.

7.
Front Mol Biosci ; 8: 666054, 2021.
Article in English | MEDLINE | ID: covidwho-1264344

ABSTRACT

The novel coronavirus pneumonia COVID-19 is characterized by all age susceptibility, which imposes a dramatic threat to the human species all over the world. According to current available data, the cytokine storm appears to be the most life-threatening symptom of severe COVID-19 cases accompanied with lung fibrosis. Galectin-3 (Gal-3), a member of soluble ß-galactoside-binding lectin families, has been implicated as a key regulator in various inflammation conditions in addition to its well-documented roles in cancer. The pro-inflammatory activity of Gal-3 in the inflammatory response and lung fibrosis of COVID-19 has been proposed by emerging studies, which suggested that inhibition of Gal-3 may represent a novel treatment approach for COVID-19 patients. Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with poor prognosis. ICC accounts for 10-25% of primary liver cancers with limited therapeutic options, which has higher incidence in Asian countries, particularly in China. Cancer patients, including ICC patients, are highly vulnerable to COVID-19 due to their impaired immune system. It is thus undoubtedly a challenge for our oncology department to establish effective treatment strategies under the influence of the COVID-19 crisis. According to our management procedures in the COVID-19 era, emergency treatment will be applied to ICC patients who are under life-threatening conditions, despite the COVID-19 infection. To the best of our knowledge, the modulatory function of Gal-3 in ICC is still barely explored to date. In order to evaluate the therapeutic potential of Gal-3 for ICC patients or those comprised with COVID-19, we herein report our preliminary investigation into roles of Gal-3 in ICC. Our results exhibited that the expression of Gal-3 was significantly up-regulated in ICC tissues, and a significant correlation was observed between its overexpression and malignant progression of ICC cells. We further discussed the activity and possible molecular mechanisms of Gal-3 in ICC, which may pave the ways for further exploring the possibility of Gal-3 as a potential therapeutic target for treating ICC patients or those with COVID-19-related conditions.

8.
Nat Metab ; 2(12): 1391-1400, 2020 12.
Article in English | MEDLINE | ID: covidwho-947555

ABSTRACT

Responsible for the ongoing coronavirus disease 19 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects host cells through binding of the viral spike protein (SARS-2-S) to the cell-surface receptor angiotensin-converting enzyme 2 (ACE2). Here we show that the high-density lipoprotein (HDL) scavenger receptor B type 1 (SR-B1) facilitates ACE2-dependent entry of SARS-CoV-2. We find that the S1 subunit of SARS-2-S binds to cholesterol and possibly to HDL components to enhance viral uptake in vitro. SR-B1 expression facilitates SARS-CoV-2 entry into ACE2-expressing cells by augmenting virus attachment. Blockade of the cholesterol-binding site on SARS-2-S1 with a monoclonal antibody, or treatment of cultured cells with pharmacological SR-B1 antagonists, inhibits HDL-enhanced SARS-CoV-2 infection. We further show that SR-B1 is coexpressed with ACE2 in human pulmonary tissue and in several extrapulmonary tissues. Our findings reveal that SR-B1 acts as a host factor that promotes SARS-CoV-2 entry and may help explain viral tropism, identify a possible molecular connection between COVID-19 and lipoprotein metabolism, and highlight SR-B1 as a potential therapeutic target to interfere with SARS-CoV-2 infection.


Subject(s)
COVID-19/metabolism , COVID-19/virology , Host-Pathogen Interactions , Lipoproteins, HDL/metabolism , SARS-CoV-2/physiology , Scavenger Receptors, Class B/metabolism , Virus Internalization , Cell Line , Cholesterol/metabolism , Disease Susceptibility , Humans , Protein Binding , Receptors, Virus , Spike Glycoprotein, Coronavirus/metabolism , Viral Tropism , Virus Attachment
9.
Nat Commun ; 11(1): 4081, 2020 08 14.
Article in English | MEDLINE | ID: covidwho-717117

ABSTRACT

The unprecedented coronavirus disease 2019 (COVID-19) epidemic has created a worldwide public health emergency, and there is an urgent need to develop an effective vaccine to control this severe infectious disease. Here, we find that a single vaccination with a replication-defective human type 5 adenovirus encoding the SARS-CoV-2 spike protein (Ad5-nCoV) protect mice completely against mouse-adapted SARS-CoV-2 infection in the upper and lower respiratory tracts. Additionally, a single vaccination with Ad5-nCoV protects ferrets from wild-type SARS-CoV-2 infection in the upper respiratory tract. This study suggests that the mucosal vaccination may provide a desirable protective efficacy and this delivery mode is worth further investigation in human clinical trials.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Viral Vaccines/immunology , Animals , Antibodies, Viral/immunology , COVID-19 , COVID-19 Vaccines , Coronavirus Infections/immunology , Disease Models, Animal , Drug Design , Female , Genetic Vectors , HEK293 Cells , Humans , Mice , Mice, Inbred BALB C , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Viral Vaccines/administration & dosage , Viral Vaccines/genetics
10.
Science ; 369(6504): 650-655, 2020 08 07.
Article in English | MEDLINE | ID: covidwho-610891

ABSTRACT

Developing therapeutics against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could be guided by the distribution of epitopes, not only on the receptor binding domain (RBD) of the Spike (S) protein but also across the full Spike (S) protein. We isolated and characterized monoclonal antibodies (mAbs) from 10 convalescent COVID-19 patients. Three mAbs showed neutralizing activities against authentic SARS-CoV-2. One mAb, named 4A8, exhibits high neutralization potency against both authentic and pseudotyped SARS-CoV-2 but does not bind the RBD. We defined the epitope of 4A8 as the N-terminal domain (NTD) of the S protein by determining with cryo-eletron microscopy its structure in complex with the S protein to an overall resolution of 3.1 angstroms and local resolution of 3.3 angstroms for the 4A8-NTD interface. This points to the NTD as a promising target for therapeutic mAbs against COVID-19.


Subject(s)
Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Betacoronavirus/immunology , Coronavirus Infections/immunology , Pneumonia, Viral/immunology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Adult , Angiotensin-Converting Enzyme 2 , Animals , Antibodies, Monoclonal/blood , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/metabolism , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/chemistry , Antibodies, Neutralizing/metabolism , Antibodies, Viral/blood , Antibodies, Viral/chemistry , Antibodies, Viral/metabolism , Antibody Affinity , Antibody Specificity , Antigens, Viral/immunology , B-Lymphocytes/immunology , COVID-19 , Chlorocebus aethiops , Coronavirus Infections/therapy , Coronavirus Nucleocapsid Proteins , Cryoelectron Microscopy , Enzyme-Linked Immunosorbent Assay , Genes, Immunoglobulin Heavy Chain , Humans , Immunologic Memory , Middle Aged , Mutation , Nucleocapsid Proteins/immunology , Pandemics , Peptidyl-Dipeptidase A/metabolism , Phosphoproteins , Pneumonia, Viral/therapy , Protein Domains , Protein Interaction Domains and Motifs/immunology , Receptors, Coronavirus , Receptors, Virus/metabolism , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism , Vero Cells , Young Adult
12.
Cell Discov ; 6: 31, 2020.
Article in English | MEDLINE | ID: covidwho-208713

ABSTRACT

COVID-19, caused by SARS-CoV-2, has recently affected over 1,200,000 people and killed more than 60,000. The key immune cell subsets change and their states during the course of COVID-19 remain unclear. We sought to comprehensively characterize the transcriptional changes in peripheral blood mononuclear cells during the recovery stage of COVID-19 by single-cell RNA sequencing technique. It was found that T cells decreased remarkably, whereas monocytes increased in patients in the early recovery stage (ERS) of COVID-19. There was an increased ratio of classical CD14++ monocytes with high inflammatory gene expression as well as a greater abundance of CD14++IL1ß+ monocytes in the ERS. CD4+ T cells and CD8+ T cells decreased significantly and expressed high levels of inflammatory genes in the ERS. Among the B cells, the plasma cells increased remarkably, whereas the naïve B cells decreased. Several novel B cell-receptor (BCR) changes were identified, such as IGHV3-23 and IGHV3-7, and isotypes (IGHV3-15, IGHV3-30, and IGKV3-11) previously used for virus vaccine development were confirmed. The strongest pairing frequencies, IGHV3-23-IGHJ4, indicated a monoclonal state associated with SARS-CoV-2 specificity, which had not been reported yet. Furthermore, integrated analysis predicted that IL-1ß and M-CSF may be novel candidate target genes for inflammatory storm and that TNFSF13, IL-18, IL-2, and IL-4 may be beneficial for the recovery of COVID-19 patients. Our study provides the first evidence of an inflammatory immune signature in the ERS, suggesting COVID-19 patients are still vulnerable after hospital discharge. Identification of novel BCR signaling may lead to the development of vaccines and antibodies for the treatment of COVID-19.

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