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2.
Nat Commun ; 13(1): 2576, 2022 05 11.
Article in English | MEDLINE | ID: covidwho-1931386

ABSTRACT

Engineered natural killer (NK) cells represent a promising option for immune therapy option due to their immediate availability in allogeneic settings. Severe acute diseases, such as COVID-19, require targeted and immediate intervention. Here we show engineering of NK cells to express (1) soluble interleukin-15 (sIL15) for enhancing their survival and (2) a chimeric antigen receptor (CAR) consisting of an extracellular domain of ACE2, targeting the spike protein of SARS-CoV-2. These CAR NK cells (mACE2-CAR_sIL15 NK cells) bind to VSV-SARS-CoV-2 chimeric viral particles as well as the recombinant SARS-CoV-2 spike protein subunit S1 leading to enhanced NK cell production of TNF-α and IFN-γ and increased in vitro and in vivo cytotoxicity against cells expressing the spike protein. Administration of mACE2-CAR_sIL15 NK cells maintains body weight, reduces viral load, and prolongs survival of transgenic mice expressing human ACE2 upon infection with live SARS-CoV-2. These experiments, and the capacity of mACE2-CAR_sIL15 NK cells to retain their activity following cryopreservation, demonstrate their potential as an allogeneic off-the-shelf therapy for COVID-19 patients who are faced with limited treatment options.


Subject(s)
COVID-19 , Receptors, Chimeric Antigen , Angiotensin-Converting Enzyme 2 , Animals , COVID-19/therapy , Humans , Interleukin-15/metabolism , Killer Cells, Natural , Mice , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
3.
J Virol ; 96(1): e0096421, 2022 01 12.
Article in English | MEDLINE | ID: covidwho-1631789

ABSTRACT

A comprehensive analysis and characterization of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection model that mimics non-severe and severe coronavirus disease 2019 (COVID-19) in humans is warranted for understating the virus and developing preventive and therapeutic agents. Here, we characterized the K18-hACE2 mouse model expressing human (h)ACE2 in mice, controlled by the human keratin 18 (K18) promoter, in the epithelia, including airway epithelial cells where SARS-CoV-2 infections typically start. We found that intranasal inoculation with higher viral doses (2 × 103 and 2 × 104 PFU) of SARS-CoV-2 caused lethality of all mice and severe damage of various organs, including lung, liver, and kidney, while lower doses (2 × 101 and 2 × 102 PFU) led to less severe tissue damage and some mice recovered from the infection. In this hACE2 mouse model, SARS-CoV-2 infection damaged multiple tissues, with a dose-dependent effect in most tissues. Similar damage was observed in postmortem samples from COVID-19 patients. Finally, the mice that recovered from infection with a low dose of virus survived rechallenge with a high dose of virus. Compared to other existing models, the K18-hACE2 model seems to be the most sensitive COVID-19 model reported to date. Our work expands the information available about this model to include analysis of multiple infectious doses and various tissues with comparison to human postmortem samples from COVID-19 patients. In conclusion, the K18-hACE2 mouse model recapitulates both severe and non-severe COVID-19 in humans being dose-dependent and can provide insight into disease progression and the efficacy of therapeutics for preventing or treating COVID-19. IMPORTANCE The pandemic of coronavirus disease 2019 (COVID-19) has reached nearly 240 million cases, caused nearly 5 million deaths worldwide as of October 2021, and has raised an urgent need for the development of novel drugs and therapeutics to prevent the spread and pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To achieve this goal, an animal model that recapitulates the features of human COVID-19 disease progress and pathogenesis is greatly needed. In this study, we have comprehensively characterized a mouse model of SARS-CoV-2 infection using K18-hACE2 transgenic mice. We infected the mice with low and high doses of SARS-CoV-2 to study the pathogenesis and survival in response to different infection patterns. Moreover, we compared the pathogenesis of the K18-hACE2 transgenic mice with that of the COVID-19 patients to show that this model could be a useful tool for the development of antiviral drugs and therapeutics.


Subject(s)
COVID-19/pathology , Disease Models, Animal , SARS-CoV-2/pathogenicity , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/immunology , COVID-19/mortality , COVID-19/virology , Humans , Immune Sera/immunology , Keratin-18/genetics , Mice , Mice, Transgenic , Promoter Regions, Genetic , Reinfection/immunology , Reinfection/mortality , Reinfection/pathology , Reinfection/virology , SARS-CoV-2/immunology , Viral Proteins/genetics , Viral Proteins/metabolism
4.
Hum Immunol ; 83(2): 119-129, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1499900

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the pandemic of coronavirus disease 2019 (COVID-19). Great international efforts have been put into the development of prophylactic vaccines and neutralizing antibodies. However, the knowledge about the B cell immune response induced by the SARS-CoV-2 virus is still limited. Here, we report a comprehensive characterization of the dynamics of immunoglobin heavy chain (IGH) repertoire in COVID-19 patients. By using next-generation sequencing technology, we examined the temporal changes in the landscape of the patient's immunological status and found dramatic changes in the IGH within the patient's immune system after the onset of COVID-19 symptoms. Although different patients have distinct immune responses to SARS-CoV-2 infection, by employing clonotype overlap, lineage expansion, and clonotype network analyses, we observed a higher clonotype overlap and substantial lineage expansion of B cell clones 2-3 weeks after the onset of illness, which is of great importance to B-cell immune responses. Meanwhile, for preferences of V gene usage during SARS-CoV-2 infection, IGHV3-74 and IGHV4-34, and IGHV4-39 in COVID-19 patients were more abundant than those of healthy controls. Overall, we present an immunological resource for SARS-CoV-2 that could promote both therapeutic development as well as mechanistic research.


Subject(s)
Antibodies, Viral/immunology , B-Lymphocytes/immunology , COVID-19/immunology , Receptors, Antigen, B-Cell/immunology , SARS-CoV-2/immunology , Adolescent , Adult , Aged, 80 and over , Antibodies, Neutralizing/immunology , Female , Humans , Immunoglobulin Heavy Chains/immunology , Male , Middle Aged
5.
Int J Environ Res Public Health ; 18(18)2021 09 15.
Article in English | MEDLINE | ID: covidwho-1409607

ABSTRACT

Lockdown measures to prevent the spread of coronavirus disease 2019 (COVID-19) resulted in the plummeting of China's overall electric-power demand and production. To date, power generation remains one of the largest carbon dioxide (CO2) emitting sectors of China on account of its high carbon intensity. Within this context, our study seeks to measure the impacts of COVID-19 lockdown on the electricity-power related carbon footprints on both generation and consumption sides. Built on statistical data of electricity generation and consumption released by the National Bureau of Statistics of China (NBSC), we calculate he nationwide electricity related CO2 emission changes in regional, economic-sectoral and technological dimensions during January-April 2020, when the strictest lock-down measures were taken in China and compare the results with the same months of the year prior. Our results show that both east and central China power grids witnessed drastic reduction (15.0% and 13.8%) in electricity-generation caused CO2 emissions; and the biggest falls of provincial-scale electricity-generation CO2 emission took place in Hubei (27.3%). Among China's electricity production mix, coal remains the biggest CO2 emitter and contributed 95.7% of the overall nationwide reduction. The most significant decline of the nationwide consumptive-electricity carbon footprint was by 10.1% in February, with the secondary economic sector the biggest contributor.


Subject(s)
COVID-19 , Carbon Dioxide/analysis , China , Coal , Communicable Disease Control , Electricity , Humans , SARS-CoV-2
6.
BMC Pulm Med ; 20(1): 233, 2020 Aug 31.
Article in English | MEDLINE | ID: covidwho-1257932

ABSTRACT

BACKGROUND: Lower respiratory tract infection (LRIs) is very common both in terms of community-acquired infection and hospital-acquired infection. Sputum and bronchoalveolar lavage fluid (BALF) are the most important specimens obtained from patients with LRI. The choice of antibiotic with which to treat LRI usually depends on the antimicrobial sensitivity of bacteria isolated from sputum and BALF. However, differences in the antimicrobial sensitivity of pathogens isolated from sputum and BALF have not been evaluated. METHODS: A retrospective study was conducted to analyze the differences between sputum and BALF samples in terms of pathogen isolation and antimicrobial sensitivity in hospitalized patients with LRI. RESULTS: Between 2013 and 2015, quality evaluation of sputum samples was not conducted before performing sputum culture; however, between 2016 and 2018, quality evaluation of sputum samples was conducted first, and only quality-assured samples were cultured. The numbers of sputum and BALF in 2013-2015 were 15,549 and 1671, while those in 2016-2018 were 12,055 and 3735, respectively. The results of pathogen culture showed that Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Staphylococcus aureus, Hemophilus influenzae, Escherichia coli, Stenotrophomonas maltophilia, and Streptococcus pneumoniae were in the top ten pathogens isolated from sputum and BALF. An antimicrobial susceptibility test showed that the susceptibility of BALF isolates to most antibiotics was higher compared with the susceptibility of sputum isolates, especially after quality control of sputum samples (2016-2018). CONCLUSIONS: Our findings suggest that caution is needed in making therapeutic choices for patients with LRI when using antimicrobial sensitivity results from sputum isolates as opposed to BALF isolates.


Subject(s)
Bacterial Infections/microbiology , Bronchoalveolar Lavage Fluid/microbiology , Microbial Sensitivity Tests , Respiratory System/microbiology , Sputum/microbiology , Anti-Bacterial Agents/therapeutic use , Bacterial Infections/epidemiology , China/epidemiology , Escherichia coli/drug effects , Escherichia coli/isolation & purification , Female , Gram-Negative Bacteria/drug effects , Gram-Negative Bacteria/isolation & purification , Gram-Positive Bacteria/drug effects , Gram-Positive Bacteria/isolation & purification , Hospitals, Teaching , Humans , Male , Retrospective Studies , Staphylococcus aureus/isolation & purification
7.
Ann Palliat Med ; 10(3): 2859-2868, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1068177

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a potentially life-threatening contagious disease which has spread all over the world. Risk factors associated with the clinical outcomes of COVID-19 pneumonia in intensive care unit (ICU) have not yet been well determined. METHODS: This was a retrospective, single-centered, observational study, in which 47 patients with confirmed COVID-19 were consecutively enrolled from February 24 to April 5, 2020. The patients were registered from the ICU of Leishenshan Hospital in Wuhan, China. Clinical characteristics and outcomes were collected and compared between survivors and non-survivors. Multivariable logistic regression was performed to analyze the risk factors of death in patients with COVID-19. RESULTS: The study cohort included 47 adult patients with an average age of 70.55±12.52 years, and 30 (63.8%) patients were men. Totally 15 (31.9%) patients died. When compared to survivors, nonsurvivors showed a higher proportion of septic shock [6 (40%) patients vs. 3 (9.4%) patients], disseminated intravascular coagulation [3 (21.4%) vs. 0], and had higher score of APACHE II (25.07±8.03 vs. 15.56±5.95), CURB-65 {3 [2-4] vs. 2 [1-3]}, Sequential Organ Failure Assessment (SOFA) {7 [5-9] vs. 3 [1-6]}, higher level of D-dimer {5.74 [2.32-18] vs 2.05 [1.09-4.00]} and neutrophil count {9.4 [7.68-14.54] vs. 5.32 [3.85-9.34]}. SOFA score (OR 1.47; 95% CI: 1.01-2.13; P=0.0042) and the lymphocyte count (OR 0.02; 95% CI: 0.00-0.86; P=0.042) on admission were independently risk factors for mortality. Patients with higher lymphocyte count (>0.63×109 /L) and lower SOFA score (≤4) on admission had a significantly better prognosis than those with lower lymphocyte count (≤0.63×109 /L) and higher SOFA score (>4) in overall survival. CONCLUSIONS: Higher SOFA score and lower lymphocyte count at admission were connected with poor prognosis of patients with COVID-19 in ICU. Lymphocyte count may serve as a promising prognostic biomarker.


Subject(s)
COVID-19/mortality , Intensive Care Units , Aged , Aged, 80 and over , COVID-19/diagnosis , China , Female , Humans , Lymphocyte Count , Male , Middle Aged , Organ Dysfunction Scores , Prognosis , Retrospective Studies , Risk Factors
8.
Eur J Med Chem ; 213: 113201, 2021 Mar 05.
Article in English | MEDLINE | ID: covidwho-1039337

ABSTRACT

The widespread nature of several viruses is greatly credited to their rapidly altering RNA genomes that enable the infection to persist despite challenges presented by host cells. Within the RNA genome of infections is RNA-dependent RNA polymerase (RdRp), which is an essential enzyme that helps in RNA synthesis by catalysing the RNA template-dependent development of phosphodiester bonds. Therefore, RdRp is an important therapeutic target in RNA virus-caused diseases, including SARS-CoV-2. In this review, we describe the promising RdRp inhibitors that have been launched or are currently in clinical studies for the treatment of RNA virus infections. Structurally, nucleoside inhibitors (NIs) bind to the RdRp protein at the enzyme active site, and nonnucleoside inhibitors (NNIs) bind to the RdRp protein at allosteric sites. By reviewing these inhibitors, more precise guidelines for the development of more promising anti-RNA virus drugs should be set, and due to the current health emergency, they will eventually be used for COVID-19 treatment.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Coronavirus RNA-Dependent RNA Polymerase/antagonists & inhibitors , Drug Repositioning , Enzyme Inhibitors/therapeutic use , Animals , Antiviral Agents/chemistry , COVID-19/epidemiology , Enzyme Inhibitors/chemistry , Humans , Nucleosides/chemistry , Nucleosides/therapeutic use , Pandemics , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology
9.
Phytomed Plus ; 1(2): 100027, 2021 May.
Article in English | MEDLINE | ID: covidwho-1032443

ABSTRACT

Background: In December 2019, a novel coronavirus, SARS-CoV-2 caused a series of acute atypical respiratory diseases worldwide. However, there is still a lack of drugs with clear curative effects, and the clinical trial research of vaccines has not been completely finished. Purpose: LH capsules are approved TCM patent medicine that are widely used for the treatment of respiratory tract infectious diseases caused by colds and flu. On April 12, 2020, LH capsules and granules were officially repurposed by the China Food and Drug Administration (CFDA) for patients with mild COVID-19 based on their safety and efficacy demonstrated through multicentre, randomized, controlled clinical trials. We hope to conduct a comprehensive review of it through modern pharmacy methods, and try to explain its possible mechanism. Methods: Using the full names of LH capsules Lianhuaqingwen, Lianhua Qingwen andSARS-COV-2, COVID-19 as the keywords of the search terms, systemically search for existing related papers in various databases such as Web of Science and PubMed. And completed the collection of clinical data in ClinicalTrials.gov and Chinese Clinical Trial Registry. Last but not least, we have sorted out the anti-inflammatory and antiviral mechanisms of LH capsules through literature and Selleck. Results: This review systematically sorted out the active ingredients in LH capsules. Furthermore, the related pharmacological and clinical trials of LH capsule on SARS-CoV-2, IAV and IBV were discussed in detail. Moreover, the present review provides the first summary of the potential molecular mechanism of specific substances in LH capsules involved in resistance to SARS-COV-2 infection and the inhibition of cytokine storm syndrome (CSS) caused by IL-6. Conclusion: This review summarizes the available reports and evidence that support the use of LH capsules as potential drug candidates for the prevention and treatment of COVID-19. However, TCM exerts its effects through multiple targets and multiple pathways, and LH capsules are not an exception. Therefore, the relevant mechanisms need to be further improved and experimentally verified.

10.
Eur J Med Chem ; 206: 112711, 2020 Nov 15.
Article in English | MEDLINE | ID: covidwho-879739

ABSTRACT

This review fully describes the coronavirus 3CLpro peptidomimetic inhibitors and nonpeptidic small molecule inhibitors developed from 2010 to 2020. Specifically, the structural characteristics, binding modes and SARs of these 3CLpro inhibitors are expounded in detail by division into two categories: peptidomimetic inhibitors mainly utilize electrophilic warhead groups to covalently bind the 3CLpro Cys145 residue and thereby achieve irreversible inhibition effects, whereas nonpeptidic small molecule inhibitors mainly interact with residues in the S1', S1, S2 and S4 pockets via hydrogen bonds, hydrophobic bonds and van der Waals forces. Based on the emerging PROTAC technology and the existing 3CLpro inhibitors, 3CLpro PROTAC degraders are hypothesised to be next-generation anti-coronavirus drugs.


Subject(s)
Antiviral Agents/pharmacology , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/therapeutic use , Coronavirus 3C Proteases , Cysteine Endopeptidases , Humans , Peptidomimetics , Protease Inhibitors/therapeutic use
11.
medrxiv; 2020.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2020.06.07.20125096

ABSTRACT

SARS-CoV-2 outbreak is a world-wide pandemic. The Spike protein plays central role in cell entry of the virus, and triggers significant immuno-response. Our understanding of the immune-response against S protein is still very limited. Herein, we constructed a peptide microarray and analyzed 55 convalescent sera, three areas with rich linear epitopes were identified. Potent neutralizing antibodies enriched from sera by 3 peptides, which do not belong to RBD were revealed.

12.
Eur J Med Chem ; 201: 112527, 2020 Sep 01.
Article in English | MEDLINE | ID: covidwho-548763

ABSTRACT

Remdesivir (GS-5734), a viral RNA-dependent RNA polymerase (RdRP) inhibitor that can be used to treat a variety of RNA virus infections, is expected to be an effective treatment for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. On May 1, 2020, The U.S. Food and Drug Administration (FDA) has granted Emergency Use Authorization (EUA) for remdesivir to treat COVID-19 patients. In light of the COVID-19 pandemic, this review presents comprehensive information on remdesivir, including information regarding the milestones, intellectual properties, anti-coronavirus mechanisms, preclinical research and clinical trials, and in particular, the chemical synthesis, pharmacology, toxicology, pharmacodynamics and pharmacokinetics of remdesivir. Furthermore, perspectives regarding the use of remdesivir for the treatment of COVID-19 are also discussed.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Adenosine Monophosphate/therapeutic use , Alanine/therapeutic use , COVID-19 , Clinical Trials as Topic , Coronavirus Infections/virology , Humans , Pandemics , Pneumonia, Viral/virology , SARS-CoV-2
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