Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 20
Filter
1.
Adv Sci (Weinh) ; : e2104333, 2022 Apr 11.
Article in English | MEDLINE | ID: covidwho-1782562

ABSTRACT

Coronavirus disease 2019 (COVID-19) remains a global public health threat. Hence, more effective and specific antivirals are urgently needed. Here, COVID-19 hyperimmune globulin (COVID-HIG), a passive immunotherapy, is prepared from the plasma of healthy donors vaccinated with BBIBP-CorV (Sinopharm COVID-19 vaccine). COVID-HIG shows high-affinity binding to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein, the receptor-binding domain (RBD), the N-terminal domain of the S protein, and the nucleocapsid protein; and blocks RBD binding to human angiotensin-converting enzyme 2 (hACE2). Pseudotyped and authentic virus-based assays show that COVID-HIG displays broad-spectrum neutralization effects on a wide variety of SARS-CoV-2 variants, including D614G, Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Kappa (B.1.617.1), Delta (B.1.617.2), and Omicron (B.1.1.529) in vitro. However, a significant reduction in the neutralization titer is detected against Beta, Delta, and Omicron variants. Additionally, assessments of the prophylactic and treatment efficacy of COVID-HIG in an Adv5-hACE2-transduced IFNAR-/- mouse model of SARS-CoV-2 infection show significantly reduced weight loss, lung viral loads, and lung pathological injury. Moreover, COVID-HIG exhibits neutralization potency similar to that of anti-SARS-CoV-2 hyperimmune globulin from pooled convalescent plasma. Overall, the results demonstrate the potential of COVID-HIG against SARS-CoV-2 infection and provide reference for subsequent clinical trials.

2.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-330174

ABSTRACT

Severe injuries following viral infection cause lung epithelial destruction with the presence of ectopic basal progenitor cells (EBCs), although the exact function of EBCs remains controversial. We and others previously showed the presence of ectopic tuft cells in the disrupted alveolar region following severe influenza infection. Here, we further revealed that the ectopic tuft cells are derived from EBCs. This process is amplified by Wnt signaling inhibition but suppressed by Notch inhibition. Further analysis revealed that p63-CreER labeled population de novo arising during regeneration includes alveolar epithelial cells when Tamoxifen was administrated after viral infection. The generation of the p63-CreER labeled alveolar cells is independent of tuft cells, demonstrating segregated differentiation paths of EBCs in lung repair. EBCs and ectopic tuft cells can also be found in the lung parenchyma post SARS-CoV-2 infection, suggesting a similar response to severe injuries in humans.

4.
J Am Chem Soc ; 144(13): 5702-5707, 2022 Apr 06.
Article in English | MEDLINE | ID: covidwho-1713118

ABSTRACT

The rapid emergence and spread of escaping mutations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has significantly challenged our efforts in fighting against the COVID-19 pandemic. A broadly neutralizing reagent against these concerning variants is thus highly desirable for the prophylactic and therapeutic treatments of SARS-CoV-2 infection. We herein report a covalent engineering strategy on protein minibinders for potent neutralization of the escaping variants such as B.1.617.2 (Delta), B.1.617.1 (Kappa), and B.1.1.529 (Omicron) through in situ cross-linking with the spike receptor binding domain (RBD). The resulting covalent minibinder (GlueBinder) exhibited enhanced blockage of RBD-human angiotensin-converting enzyme 2 (huACE2) interaction and more potent neutralization effect against the Delta variant than its noncovalent counterpart as demonstrated on authentic virus. By leveraging the covalent chemistry against escaping mutations, our strategy may be generally applicable for restoring and enhancing the potency of neutralizing antibodies to SARS-CoV-2 and other rapidly evolving viral targets.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/drug therapy , Humans , Neutralization Tests , Pandemics , Protein Binding , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics
5.
Adv Sci (Weinh) ; 9(7): e2104192, 2022 03.
Article in English | MEDLINE | ID: covidwho-1589262

ABSTRACT

Coronavirus disease 2019 (COVID-19) patients with impact on skin and hair loss are reported. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is detected in the skin of some patients; however, the detailed pathological features of skin tissues from patients infected with SARS-CoV-2 at a molecular level are limited. Especially, the ability of SARS-CoV-2 to infect skin cells and impact their function is not well understood. A proteome map of COVID-19 skin is established here and the susceptibility of human-induced pluripotent stem cell (hiPSC)-derived skin organoids with hair follicles and nervous system is investigated, to SARS-CoV-2 infection. It is shown that KRT17+ hair follicles can be infected by SARS-CoV-2 and are associated with the impaired development of hair follicles and epidermis. Different types of nervous system cells are also found to be infected, which can lead to neuron death. Findings from the present work provide evidence for the association between COVID-19 and hair loss. hiPSC-derived skin organoids are also presented as an experimental model which can be used to investigate the susceptibility of skin cells to SARS-CoV-2 infection and can help identify various pathological mechanisms and drug screening strategies.


Subject(s)
COVID-19/physiopathology , Induced Pluripotent Stem Cells/cytology , Models, Biological , Organoids/cytology , Skin/cytology , COVID-19/virology , Hair Follicle/virology , Humans , Nervous System/virology , Proteomics , SARS-CoV-2/isolation & purification
7.
Cell Discov ; 6(1): 84, 2020 Nov 13.
Article in English | MEDLINE | ID: covidwho-1387260
10.
Cell Discov ; 7(1): 57, 2021 Jul 27.
Article in English | MEDLINE | ID: covidwho-1328842

ABSTRACT

As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to threaten public health worldwide, the development of effective interventions is urgently needed. Neutralizing antibodies (nAbs) have great potential for the prevention and treatment of SARS-CoV-2 infection. In this study, ten nAbs were isolated from two phage-display immune libraries constructed from the pooled PBMCs of eight COVID-19 convalescent patients. Eight of them, consisting of heavy chains encoded by the immunoglobulin heavy-chain gene-variable region (IGHV)3-66 or IGHV3-53 genes, recognized the same epitope on the receptor-binding domain (RBD), while the remaining two bound to different epitopes. Among the ten antibodies, 2B11 exhibited the highest affinity and neutralization potency against the original wild-type (WT) SARS-CoV-2 virus (KD = 4.76 nM for the S1 protein, IC50 = 6 ng/mL for pseudoviruses, and IC50 = 1 ng/mL for authentic viruses), and potent neutralizing ability against B.1.1.7 pseudoviruses. Furthermore, 1E10, targeting a distinct epitope on RBD, exhibited different neutralization efficiency against WT SARS-CoV-2 and its variants B.1.1.7, B.1.351, and P.1. The crystal structure of the 2B11-RBD complexes revealed that the epitope of 2B11 highly overlaps with the ACE2-binding site. The in vivo experiment of 2B11 using AdV5-hACE2-transduced mice showed encouraging therapeutic and prophylactic efficacy against SARS-CoV-2. Taken together, our results suggest that the highly potent SARS-CoV-2-neutralizing antibody, 2B11, could be used against the WT SARS-CoV-2 and B.1.1.7 variant, or in combination with a different epitope-targeted neutralizing antibody, such as 1E10, against SARS-CoV-2 variants.

11.
Front Psychol ; 12: 626547, 2021.
Article in English | MEDLINE | ID: covidwho-1325556

ABSTRACT

Objective: The COVID-19 epidemic has generated great stress throughout healthcare workers (HCWs). The situation of HCWs should be fully and timely understood. The aim of this meta-analysis is to determine the psychological impact of COVID-19 pandemic on health care workers. Method: We searched the original literatures published from 1 Nov 2019 to 20 Sep 2020 in electronic databases of PUBMED, EMBASE and WEB OF SCIENCE. Forty-seven studies were included in the meta-analysis with a combined total of 81,277 participants. Results: The pooled prevalence of anxiety is 37% (95% CI 0.31-0.42, I2 = 99.9%) from 44 studies. Depression is estimated in 39 studies, and the pooled prevalence of depression is 36% (95% CI 0.31-0.41, I2 = 99.6%). There are 10 studies reported the prevalence of insomnia, and the overall prevalence of insomnia is 32% (95% CI 0.23-0.42, I2 = 99.5%). The subgroup analysis showed a higher incidence of anxiety and depression among women and the frontline HCWs compared to men and non-frontline HCWs respectively. Conclusions: The COVID-19 pandemic has caused heavy psychological impact among healthcare professionals especially women and frontline workers. Timely psychological counseling and intervention ought to be implemented for HCWs in order to alleviate their anxiety and improve their general mental health.

12.
Signal Transduct Target Ther ; 6(1): 195, 2021 05 17.
Article in English | MEDLINE | ID: covidwho-1232065

ABSTRACT

B cell response plays a critical role against SARS-CoV-2 infection. However, little is known about the diversity and frequency of the paired SARS-CoV-2 antigen-specific BCR repertoire after SARS-CoV-2 infection. Here, we performed single-cell RNA sequencing and VDJ sequencing using the memory and plasma B cells isolated from five convalescent COVID-19 patients, and analyzed the spectrum and transcriptional heterogeneity of antibody immune responses. Via linking BCR to antigen specificity through sequencing (LIBRA-seq), we identified a distinct activated memory B cell subgroup (CD11chigh CD95high) had a higher proportion of SARS-CoV-2 antigen-labeled cells compared with memory B cells. Our results revealed the diversity of paired BCR repertoire and the non-stochastic pairing of SARS-CoV-2 antigen-specific immunoglobulin heavy and light chains after SARS-CoV-2 infection. The public antibody clonotypes were shared by distinct convalescent individuals. Moreover, several antibodies isolated by LIBRA-seq showed high binding affinity against SARS-CoV-2 receptor-binding domain (RBD) or nucleoprotein (NP) via ELISA assay. Two RBD-reactive antibodies C14646P3S and C2767P3S isolated by LIBRA-seq exhibited high neutralizing activities against both pseudotyped and authentic SARS-CoV-2 viruses in vitro. Our study provides fundamental insights into B cell response following SARS-CoV-2 infection at the single-cell level.


Subject(s)
B-Lymphocytes/immunology , COVID-19/immunology , Convalescence , Immunologic Memory , RNA-Seq , SARS-CoV-2/immunology , Animals , B-Lymphocytes/pathology , COVID-19/genetics , COVID-19/pathology , Cell Line, Tumor , Cell Separation , Chlorocebus aethiops , HEK293 Cells , Humans , SARS-CoV-2/genetics , Vero Cells
13.
PLoS Biol ; 19(5): e3001209, 2021 05.
Article in English | MEDLINE | ID: covidwho-1219261

ABSTRACT

The ongoing Coronavirus Disease 2019 (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) threatens global public health and economy unprecedentedly, requiring accelerating development of prophylactic and therapeutic interventions. Molecular understanding of neutralizing antibodies (NAbs) would greatly help advance the development of monoclonal antibody (mAb) therapy, as well as the design of next generation recombinant vaccines. Here, we applied H2L2 transgenic mice encoding the human immunoglobulin variable regions, together with a state-of-the-art antibody discovery platform to immunize and isolate NAbs. From a large panel of isolated antibodies, 25 antibodies showed potent neutralizing activities at sub-nanomolar levels by engaging the spike receptor-binding domain (RBD). Importantly, one human NAb, termed PR1077, from the H2L2 platform and 2 humanized NAb, including PR953 and PR961, were further characterized and subjected for subsequent structural analysis. High-resolution X-ray crystallography structures unveiled novel epitopes on the receptor-binding motif (RBM) for PR1077 and PR953, which directly compete with human angiotensin-converting enzyme 2 (hACE2) for binding, and a novel non-blocking epitope on the neighboring site near RBM for PR961. Moreover, we further tested the antiviral efficiency of PR1077 in the Ad5-hACE2 transduction mouse model of COVID-19. A single injection provided potent protection against SARS-CoV-2 infection in either prophylactic or treatment groups. Taken together, these results shed light on the development of mAb-related therapeutic interventions for COVID-19.


Subject(s)
Antibodies, Neutralizing/immunology , COVID-19/virology , SARS-CoV-2/immunology , Animals , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/metabolism , Antibodies, Neutralizing/metabolism , Antibodies, Neutralizing/ultrastructure , Antibodies, Viral/immunology , COVID-19/epidemiology , COVID-19/immunology , COVID-19/metabolism , Epitopes/immunology , Humans , Mice , Mice, Transgenic , Neutralization Tests , Pandemics , Protein Binding , Protein Domains , Receptors, Virus/immunology , Spike Glycoprotein, Coronavirus/immunology
14.
Virol Sin ; 35(6): 776-784, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-1217480

ABSTRACT

The recent outbreak of novel coronavirus pneumonia (COVID-19) caused by a new coronavirus has posed a great threat to public health. Identifying safe and effective antivirals is of urgent demand to cure the huge number of patients. Virus-encoded proteases are considered potential drug targets. The human immunodeficiency virus protease inhibitors (lopinavir/ritonavir) has been recommended in the global Solidarity Trial in March launched by World Health Organization. However, there is currently no experimental evidence to support or against its clinical use. We evaluated the antiviral efficacy of lopinavir/ritonavir along with other two viral protease inhibitors in vitro, and discussed the possible inhibitory mechanism in silico. The in vitro to in vivo extrapolation was carried out to assess whether lopinavir/ritonavir could be effective in clinical. Among the four tested compounds, lopinavir showed the best inhibitory effect against the novel coronavirus infection. However, further in vitro to in vivo extrapolation of pharmacokinetics suggested that lopinavir/ritonavir could not reach effective concentration under standard dosing regimen [marketed as Kaletra®, contained lopinavir/ritonavir (200 mg/50 mg) tablets, recommended dosage is 400 mg/10 mg (2 tablets) twice daily]. This research concluded that lopinavir/ritonavir should be stopped for clinical use due to the huge gap between in vitro IC50 and free plasma concentration. Nevertheless, the structure-activity relationship analysis of the four inhibitors provided further information for de novel design of future viral protease inhibitors of SARS-CoV-2.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Lopinavir/pharmacology , Ritonavir/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology , Viral Protease Inhibitors/pharmacology , Animals , Antiviral Agents/chemistry , COVID-19/blood , COVID-19/virology , Cell Line , Chlorocebus aethiops , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Drug Combinations , Humans , Lopinavir/blood , Male , Molecular Docking Simulation , Ritonavir/blood , Vero Cells , Viral Protease Inhibitors/chemistry
15.
Asian J Psychiatr ; 56: 102533, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1064771

ABSTRACT

AIM: This study aimed to investigate and monitor the mental health status of pregnant women during the COVID-19 pandemic. MATERIALS AND METHODS: The meta-analysis was used to study the literatures on the psychology of pregnant women in four databases until Sep 27, 2020. RESULTS: A total of 19 articles were included in the final meta-analysis. The overall prevalence of anxiety was 42 % (95 %CI 26 %-57 %) with substantial heterogeneity (I2 = 99.6 %). The overall prevalence of depression was 25 % (95 %CI 20 %-31 %) with substantial heterogeneity (I2 = 97.9 %). Age, family economic status, social support, and physical activity seem to correlate with the mental health status of pregnant women. CONCLUSION: The prevalence of anxiety and depression among pregnant women increased significantly during the COVID-19 epidemic. Pregnant women are more concerned about others than themselves during COVID-19, and younger pregnant women seem to be more prone to anxiety, while social support and physical activity can reduce the likelihood of anxiety and depression. It is necessary to take some psychological intervention measures for pregnant women to help them go through this special period safely and smoothly.


Subject(s)
Anxiety/epidemiology , COVID-19 , Depression/epidemiology , Pregnancy Complications/epidemiology , Age Factors , Anxiety/psychology , Depression/psychology , Economic Status , Exercise/psychology , Female , Humans , Pregnancy , Pregnancy Complications/psychology , Pregnant Women/psychology , SARS-CoV-2 , Social Support
17.
J Psychiatr Res ; 135: 37-46, 2021 03.
Article in English | MEDLINE | ID: covidwho-1009693

ABSTRACT

Only a few studies investigated the impact of quarantine on anxiety of general population during a second wave of COVID-19 breakout. We aimed to compare anxiety levels of quarantined and non-quarantined people and investigate factors affecting anxiety during the second COVID-19 pandemic. A total of 1837 participants were included in this cross-sectional study. Anxiety was measured by the State-Trait Anxiety Inventory (STAI). Participants were divided into the quarantined group (QG) and non-quarantined group (Non-QG). The mean STAI-S score in the QG was significantly higher than Non-QG (41.8 ± 11.2 vs 40.01 ± 9.9), so was the proportion of severe state anxiety (11.6% vs 5.5%). Males in the QG were significantly more anxious than females evaluated by both STAI-S and STAI-T. High income was independent protective factors while moderate or bad health status and high trait anxiety level were independent risk factors for severe state anxiety. In conclusion, the COVID-19 confinement could significantly increase anxiety of quarantined people. Males were more vulnerable to the quarantine of COVID-19 with significantly increased anxiety level than females. The results suggest that attention should be paid to anxiety during a second round of quarantine due to COVID-19 and are of help in planning psychological interventions.


Subject(s)
Anxiety Disorders/epidemiology , Anxiety/epidemiology , COVID-19/epidemiology , COVID-19/prevention & control , Quarantine/statistics & numerical data , Adolescent , Adult , China/epidemiology , Cross-Sectional Studies , Female , Humans , Male , Middle Aged , Young Adult
18.
J Virol ; 94(6)2020 02 28.
Article in English | MEDLINE | ID: covidwho-827743

ABSTRACT

TER94 is a multifunctional AAA+ ATPase crucial for diverse cellular processes, especially protein quality control and chromatin dynamics in eukaryotic organisms. Many viruses, including coronavirus, herpesvirus, and retrovirus, coopt host cellular TER94 for optimal viral invasion and replication. Previous proteomics analysis identified the association of TER94 with the budded virions (BVs) of baculovirus, an enveloped insect large DNA virus. Here, the role of TER94 in the prototypic baculovirus Autographa californica multiple nucleopolyhedrovirus (AcMNPV) life cycle was investigated. In virus-infected cells, TER94 accumulated in virogenic stroma (VS) at the early stage of infection and subsequently partially rearranged in the ring zone region. In the virions, TER94 was associated with the nucleocapsids of both BV and occlusion-derived virus (ODV). Inhibition of TER94 ATPase activity significantly reduced viral DNA replication and BV production. Electron/immunoelectron microscopy revealed that inhibition of TER94 resulted in the trapping of nucleocapsids within cytoplasmic vacuoles at the nuclear periphery for BV formation and blockage of ODV envelopment at a premature stage within infected nuclei, which appeared highly consistent with its pivotal function in membrane biogenesis. Further analyses showed that TER94 was recruited to the VS or subnuclear structures through interaction with viral early proteins LEF3 and helicase, whereas inhibition of TER94 activity blocked the proper localization of replication-related viral proteins and morphogenesis of VS, providing an explanation for its role in viral DNA replication. Taken together, these data indicated the crucial functions of TER94 at multiple steps of the baculovirus life cycle, including genome replication, BV formation, and ODV morphogenesis.IMPORTANCE TER94 constitutes an important AAA+ ATPase that associates with diverse cellular processes, including protein quality control, membrane fusion of the Golgi apparatus and endoplasmic reticulum network, nuclear envelope reformation, and DNA replication. To date, little is known regarding the role(s) of TER94 in the baculovirus life cycle. In this study, TER94 was found to play a crucial role in multiple steps of baculovirus infection, including viral DNA replication and BV and ODV formation. Further evidence showed that the membrane fission/fusion function of TER94 is likely to be exploited by baculovirus for virion morphogenesis. Moreover, TER94 could interact with the viral early proteins LEF3 and helicase to transport and further recruit viral replication-related proteins to establish viral replication factories. This study highlights the critical roles of TER94 as an energy-supplying chaperon in the baculovirus life cycle and enriches our knowledge regarding the biological function of this important host factor.


Subject(s)
Adenosine Triphosphatases/metabolism , Nucleocapsid/metabolism , Nucleopolyhedroviruses/physiology , Virus Replication , Animals , Cell Nucleus/virology , Cytoplasm/virology , DNA Helicases/metabolism , DNA, Viral/biosynthesis , DNA-Binding Proteins/metabolism , Host-Pathogen Interactions , Sf9 Cells/virology , Vacuoles/virology , Viral Proteins/metabolism , Virion
19.
ACS Infect Dis ; 6(9): 2524-2531, 2020 09 11.
Article in English | MEDLINE | ID: covidwho-695395

ABSTRACT

The discovery of novel drug candidates with anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) potential is critical for the control of the global COVID-19 pandemic. Artemisinin, an old antimalarial drug derived from Chinese herbs, has saved millions of lives. Artemisinins are a cluster of artemisinin-related drugs developed for the treatment of malaria and have been reported to have multiple pharmacological activities, including anticancer, antiviral, and immune modulation. Considering the reported broad-spectrum antiviral potential of artemisinins, researchers are interested in whether they could be used to combat COVID-19. We systematically evaluated the anti-SARS-CoV-2 activities of nine artemisinin-related compounds in vitro and carried out a time-of-drug-addition assay to explore their antiviral mode of action. Finally, a pharmacokinetic prediction model was established to predict the therapeutic potential of selected compounds against COVID-19. Arteannuin B showed the highest anti-SARS-CoV-2 potential with an EC50 of 10.28 ± 1.12 µM. Artesunate and dihydroartemisinin showed similar EC50 values of 12.98 ± 5.30 µM and 13.31 ± 1.24 µM, respectively, which could be clinically achieved in plasma after intravenous administration. Interestingly, although an EC50 of 23.17 ± 3.22 µM was not prominent among the tested compounds, lumefantrine showed therapeutic promise due to high plasma and lung drug concentrations after multiple dosing. Further mode of action analysis revealed that arteannuin B and lumefantrine acted at the post-entry step of SARS-CoV-2 infection. This research highlights the anti-SARS-CoV-2 potential of artemisinins and provides leading candidates for anti-SARS-CoV-2 drug research and development.


Subject(s)
Antiviral Agents/pharmacology , Artemisinins/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Animals , Antimalarials/pharmacology , COVID-19 , Chlorocebus aethiops , Drug Discovery , Drug Repositioning , Drugs, Chinese Herbal/pharmacology , Pandemics , SARS-CoV-2 , Vero Cells
SELECTION OF CITATIONS
SEARCH DETAIL