Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 8 de 8
Filter
1.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-332336

ABSTRACT

Recent studies have revealed the unique virological characteristics of Omicron, the newest SARS-CoV-2 variant of concern, such as pronounced resistance to vaccine-induced neutralizing antibodies, less efficient cleavage of the spike protein, and poor fusogenicity. However, it remains unclear which mutation(s) in the spike protein determine the virological characteristics of Omicron. Here, we show that the representative characteristics of the Omicron spike are determined by its receptor-binding domain. Interestingly, the molecular phylogenetic analysis revealed that the acquisition of the spike S375F mutation was closely associated with the explosive spread of Omicron in the human population. We further elucidate that the F375 residue forms an interprotomer pi-pi interaction with the H505 residue in another protomer in the spike trimer, which confers the attenuated spike cleavage efficiency and fusogenicity of Omicron. Our data shed light on the evolutionary events underlying Omicron emergence at the molecular level. Highlights Omicron spike receptor binding domain determines virological characteristics Spike S375F mutation results in the poor spike cleavage and fusogenicity in Omicron Acquisition of the spike S375F mutation triggered the explosive spread of Omicron F375-H505-mediated π-π interaction in the spike determines the phenotype of Omicron

2.
J Immunotoxicol ; 18(1): 23-29, 2021 12.
Article in English | MEDLINE | ID: covidwho-1593522

ABSTRACT

The coronavirus SARS-CoV-2 of 2019 (COVID-19) causes a pandemic that has been diagnosed in more than 70 million people worldwide. Mild-to-moderate COVID-19 symptoms include coughing, fever, myalgia, shortness of breath, and acute inflammatory lung injury (ALI). In contrast, acute respiratory distress syndrome (ARDS) and respiratory failure occur in patients diagnosed with severe COVID-19. ARDS is mediated, at least in part, by a dysregulated inflammatory response due to excessive levels of circulating cytokines, a condition known as the "cytokine-storm syndrome." Currently, there are FDA-approved therapies that attenuate the dysregulated inflammation that occurs in COVID-19 patients, such as dexamethasone or other corticosteroids and IL-6 inhibitors, including sarilumab, tocilizumab, and siltuximab. However, the efficacy of these treatments have been shown to be inconsistent. Compounds that activate the vagus nerve-mediated cholinergic anti-inflammatory reflex, such as the α7 nicotinic acetylcholine receptor agonist, GTS-21, attenuate ARDS/inflammatory lung injury by decreasing the extracellular levels of high mobility group box-1 (HMGB1) in the airways and the circulation. It is possible that HMGB1 may be an important mediator of the "cytokine-storm syndrome." Notably, high plasma levels of HMGB1 have been reported in patients diagnosed with severe COVID-19, and there is a significant negative correlation between HMGB1 plasma levels and clinical outcomes. Nicotine can activate the cholinergic anti-inflammatory reflex, which attenuates the up-regulation and the excessive release of pro-inflammatory cytokines/chemokines. Therefore, we hypothesize that low molecular weight compounds that activate the cholinergic anti-inflammatory reflex, such as nicotine or GTS-21, may represent a potential therapeutic approach to attenuate the dysregulated inflammatory responses in patients with severe COVID-19.


Subject(s)
Benzylidene Compounds/pharmacology , COVID-19/drug therapy , Cholinergic Agents/pharmacology , Inflammation/drug therapy , Nicotine/metabolism , Pyridines/pharmacology , SARS-CoV-2/physiology , Tobacco Use Disorder/drug therapy , Antibodies, Monoclonal, Humanized/therapeutic use , Cigarette Smoking/adverse effects , Dexamethasone/therapeutic use , HMGB1 Protein/blood , Humans , Pandemics , alpha7 Nicotinic Acetylcholine Receptor/agonists
3.
Cell Rep ; 38(2): 110218, 2022 01 11.
Article in English | MEDLINE | ID: covidwho-1588140

ABSTRACT

SARS-CoV-2 Lambda, a variant of interest, has spread in some South American countries; however, its virological features and evolutionary traits remain unclear. In this study, we use pseudoviruses and reveal that the spike protein of the Lambda variant is more infectious than that of other variants due to the T76I and L452Q mutations. The RSYLTPGD246-253N mutation, a unique 7-amino acid deletion in the N-terminal domain of the Lambda spike protein, is responsible for evasion from neutralizing antibodies and further augments antibody-mediated enhancement of infection. Although this mutation generates a nascent N-linked glycosylation site, the additional N-linked glycan is dispensable for the virological property conferred by this mutation. Since the Lambda variant has dominantly spread according to the increasing frequency of the isolates harboring the RSYLTPGD246-253N mutation, our data suggest that the RSYLTPGD246-253N mutation is closely associated with the substantial spread of the Lambda variant in South America.


Subject(s)
COVID-19/immunology , Immunity/immunology , SARS-CoV-2/immunology , Adult , Aged , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Cell Line , Female , Glycosylation , HEK293 Cells , Humans , Male , Middle Aged , Mutation/immunology , Spike Glycoprotein, Coronavirus/immunology
4.
Nature ; 602(7896): 300-306, 2022 02.
Article in English | MEDLINE | ID: covidwho-1532072

ABSTRACT

During the current coronavirus disease 2019 (COVID-19) pandemic, a variety of mutations have accumulated in the viral genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and, at the time of writing, four variants of concern are considered to be potentially hazardous to human society1. The recently emerged B.1.617.2/Delta variant of concern is closely associated with the COVID-19 surge that occurred in India in the spring of 2021 (ref. 2). However, the virological properties of B.1.617.2/Delta remain unclear. Here we show that the B.1.617.2/Delta variant is highly fusogenic and notably more pathogenic than prototypic SARS-CoV-2 in infected hamsters. The P681R mutation in the spike protein, which is highly conserved in this lineage, facilitates cleavage of the spike protein and enhances viral fusogenicity. Moreover, we demonstrate that the P681R-bearing virus exhibits higher pathogenicity compared with its parental virus. Our data suggest that the P681R mutation is a hallmark of the virological phenotype of the B.1.617.2/Delta variant and is associated with enhanced pathogenicity.


Subject(s)
COVID-19/virology , Membrane Fusion , Mutation , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/genetics , Amino Acid Substitution , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/epidemiology , Cricetinae , Giant Cells/metabolism , Giant Cells/virology , Male , Mesocricetus , Phylogeny , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , Virulence/genetics , Virus Replication
5.
Antioxidants (Basel) ; 10(1)2021 Jan 19.
Article in English | MEDLINE | ID: covidwho-1042079

ABSTRACT

Supplemental oxygen therapy with supraphysiological concentrations of oxygen (hyperoxia; >21% O2) is a life-saving intervention for patients experiencing respiratory distress. However, prolonged exposure to hyperoxia can compromise bacterial clearance processes, due to oxidative stress-mediated impairment of macrophages, contributing to the increased susceptibility to pulmonary infections. This study reports that the activation of the α7 nicotinic acetylcholine receptor (α7nAChR) with the delete allosteric agonistic-positive allosteric modulator, GAT107, decreases the bacterial burden in mouse lungs by improving hyperoxia-induced lung redox imbalance. The incubation of RAW 264.7 cells with GAT107 (3.3 µM) rescues hyperoxia-compromised phagocytic functions in cultured macrophages, RAW 264.7 cells, and primary bone marrow-derived macrophages. Similarly, GAT107 (3.3 µM) also attenuated oxidative stress in hyperoxia-exposed macrophages, which prevents oxidation and hyper-polymerization of phagosome filamentous actin (F-actin) from oxidation. Furthermore, GAT107 (3.3 µM) increases the (1) activity of superoxide dismutase 1; (2) activation of Nrf2 and (3) the expression of heme oxygenase-1 (HO-1) in macrophages exposed to hyperoxia. Overall, these data suggest that the novel α7nAChR compound, GAT107, could be used to improve host defense functions in patients, such as those with COVID-19, who are exposed to prolonged periods of hyperoxia.

6.
Pers Ubiquitous Comput ; : 1-17, 2021 Jan 09.
Article in English | MEDLINE | ID: covidwho-1033082

ABSTRACT

Novel coronavirus pneumonia in 17 city (Hubei) provinces was analyzed by using the principle of thermodynamics. A thermodynamic imaging model of infectious diseases was established to calculate the cumulative superimposed density of epidemic in 17 cities (prefectures). An evaluation rule of urban risk grade is established and evaluates the COVID-19 risk of 17 cities. The results show that (1) the higher the superimposed density of urban epidemic, the more infected people. (2) In the incubation stage, the thermodynamic imaging shows a point distribution, random walk, and outward diffusion trend. In the initial stage, the color of thermodynamic imaging gradually deepened and the range gradually expanded. During the burst stage, the thermodynamic imaging color deepens rapidly and the scope expands rapidly. In the stable stage, the thermodynamic imaging color becomes darkest and the range is extended to the pole. (3) According to the situation of COVID-19 transmission in Hubei Province, the cumulative superimposed density of Wuhan epidemic is far more than 10,000, ranking as "highest-risk." Xiaogan and other 10 cities have a cumulative superimposed density within the range of [1000, 10,000], ranking as "high-risk." Shiyan and other 5 cities have accumulated superimposed density values within the range of [100, 1000], ranking as "medium-risk." Shennongjia cumulative superimposed density value is less than 100, and the level is "low-risk."

7.
Br J Pharmacol ; 177(18): 4147-4165, 2020 09.
Article in English | MEDLINE | ID: covidwho-592492

ABSTRACT

BACKGROUND AND PURPOSE: Immunosuppression is the predominant cause of mortality for sepsis because of failure to eradicate pathogens. No effective and specific drugs capable of reversing immunosuppression are clinically available. Evidences implicate the involvement of the vitamin D receptor (NR1I1) in sepsis-induced immunosuppression. The anti-malarial artesunate was investigated to determine action on sepsis-induced immunosuppression. EXPERIMENTAL APPROACH: The effect of artesunate on sepsis-induced immunosuppression was investigated in mice and human and mice cell lines. Bioinformatics predicted vitamin D receptor as a candidate target for artesunate, which was then identified using PCR and immunoblotting. Vdr, Atg16l1 and NF-κB p65 were modified to investigate artesunate 's effect on pro-inflammatory cytokines release, bacterial clearance and autophagy activities in sepsis-induced immunosuppression. KEY RESULTS: Artesunate significantly reduced the mortality of caecal ligation and puncture (CLP)-induced sepsis immunosuppression mice challenged with Pseudomonas aeruginosa and enhanced pro-inflammatory cytokine release and bacterial clearance to reverse sepsis-induced immunosuppression in vivo and in vitro. Mechanistically, artesunate interacted with vitamin D receptor, inhibiting its nuclear translocation, which influenced ATG16L1 transcription and subsequent autophagy activity. Artesunate inhibited the physical interaction between vitamin D receptor and NF-κB p65 in LPS-tolerant macrophages and then promoted the nuclear translocation of NF-κB p65, which activated the transcription of NF-κB p65 target genes such as pro-inflammatory cytokines. CONCLUSION AND IMPLICATIONS: Our findings provide evidence that artesunate interacted with vitamin D receptor to reverse sepsis-induced immunosuppression in an autophagy and NF-κB-dependent manner, highlighting a novel approach for sepsis treatment and drug repurposing of artesunate has a bidirectional immunomodulator.


Subject(s)
Artesunate , Autophagy , Receptors, Calcitriol , Sepsis , Animals , Artesunate/pharmacology , Female , Male , Mice , Mice, Inbred BALB C , NF-kappa B , Receptors, Calcitriol/drug effects , Sepsis/drug therapy
8.
Integr Med Res ; 9(3): 100449, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-591822

ABSTRACT

BACKGROUND: During the COVID-19 epidemic period, Traditional Chinese Medicine (TCM) course for international students of Medical Bachelor, Bachelor of Surgery (MBBS) program in Zhejiang University has shifted from traditional classroom to online environment. This study aimed to investigate MBBS international students' perception on online TCM course, and to assess the online learning efficacy. METHODS: A total of 84 MBBS international students attending course of "Basic Traditional Chinese Medicine" during 2020 academic years at Zhejiang University were enrolled in this study. A quantitative questionnaire was respectively completed before and after the TCM course using a pretest-post-test design. By means of two online learning platforms, Learning in ZJU and DingTalk, TCM course was broadcast in both live and archived format to students. RESULTS: A total of 48 participants completed both baseline and follow-up questionnaires. The majority of participants preferred face-to-face classroom learning (26, 54.17% of total) when compared with online learning. Students felt that the course had brought in much benefits (mean 3.88, SD 0.87), and they were satisfied with the course content (mean 3.83, SD 0.95). Students' TCM related knowledge and their behaviors of discussion and consulting were significantly improved by online TCM course (all P < 0.001). Students' awareness of the necessity of TCM education and their feeling of difficulty in learning TCM were significantly strengthened (P = 0.042, 0.025, respectively). CONCLUSION: Online learning is a good alternative for TCM course of MBBS international students when classroom learning is suspended, whereas it cannot replace the need for onsite and face-to-face learning.

SELECTION OF CITATIONS
SEARCH DETAIL