Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 33
Filter
1.
Commun Biol ; 5(1): 483, 2022 05 19.
Article in English | MEDLINE | ID: covidwho-1852521

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ORF6 is an antagonist of interferon (IFN)-mediated antiviral signaling, achieved through the prevention of STAT1 nuclear localization. However, the exact mechanism through which ORF6 prevents STAT1 nuclear trafficking remains unclear. Herein, we demonstrate that ORF6 directly binds to STAT1 with or without IFN stimulation, resulting in the nuclear exclusion of STAT1. ORF6 also recognizes importin α subtypes with different modes, in particular, high affinity to importin α1 but a low affinity to importin α5. Although ORF6 potentially disrupts the importin α/importin ß1-mediated nuclear transport, thereby suppressing the nuclear translocation of the other classical nuclear localization signal-containing cargo proteins, the inhibitory effect of ORF6 is modest when compared with that of STAT1. The results indicate that the drastic nuclear exclusion of STAT1 is attributed to the specific binding with ORF6, which is a distinct strategy for the importin α1-mediated pathway. Combined with the results from a newly-produced replicon system and a hamster model, we conclude that SARS-CoV-2 ORF6 acts as a virulence factor via regulation of nucleocytoplasmic trafficking to accelerate viral replication, resulting in disease progression.


Subject(s)
COVID-19 , SARS-CoV-2 , Viral Proteins/metabolism , Animals , Antiviral Agents , Biological Transport , Cricetinae , Viral Proteins/genetics , Virus Replication , alpha Karyopherins/genetics , alpha Karyopherins/metabolism
2.
J Med Virol ; 94(8): 3982-3987, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1802454

ABSTRACT

There is a potential risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread through human contact with seafood and the inanimate materials contaminated by the virus. In this study, we examined the stability of the virus in artificial seawater (ASW) and on the surface of selected materials. SARS-CoV-2 (3.75 log10 TCID50 ) in ASW at 22℃ maintained infectious about 3 days and at 4℃ the virus survived more than 7 days. It should be noticed that viable virus at high titer (5.50 log10 TCID50 ) may survive more than 20 days in ASW at 4℃ and for 7 days at 22℃. SARS-CoV-2 on stainless steel and plastic bag maintained infectious for 3 days, and on nonwoven fabric for 1 day at 22℃. In addition, the virus remained infectious for 9 days on stainless steel and non-woven fabric, and on plastic bag for 12 days at 4℃. It is important to highlight the role of inanimate material surfaces as a source of infection and the necessity for surface decontamination and disinfection.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Plastics , Seawater , Stainless Steel
3.
Nature ; 604(7905): 298-303, 2022 04.
Article in English | MEDLINE | ID: covidwho-1795722

ABSTRACT

Achiral sulfur functional groups, such as sulfonamide, sulfone, thiol and thioether, are common in drugs and natural products. By contrast, chiral sulfur functional groups are often neglected as pharmacophores1-3, although sulfoximine, with its unique physicochemical and pharmacokinetic properties4,5, has been recently incorporated into several clinical candidates. Thus, other sulfur stereogenic centres, such as sulfinate ester, sulfinamide, sulfonimidate ester and sulfonimidamide, have started to attract attention. The diversity and complexity of these sulfur stereogenic centres have the potential to expand the chemical space for drug discovery6-10. However, the installation of these structures enantioselectively into drug molecules is highly challenging. Here we report straightforward access to enantioenriched sulfinate esters via asymmetric condensation of prochiral sulfinates and alcohols using pentanidium as an organocatalyst. We successfully coupled a wide range of sulfinates and bioactive alcohols stereoselectively. The initial sulfinates can be prepared from existing sulfone and sulfonamide drugs, and the resulting sulfinate esters are versatile for transformations to diverse chiral sulfur pharmacophores. Through late-stage diversification11,12 of celecoxib and other drug derivatives, we demonstrate the viability of this unified approach towards sulfur stereogenic centres.

5.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-315723

ABSTRACT

The pandemic of COVID-19 caused by SARS-CoV-2 has posed serious threats to global health and economy, thus calling for the development of safe and effective vaccines. The receptor-binding domain (RBD) in the spike protein of SARS-CoV-2 is responsible for its binding to ACE2 receptor. It contains multiple dominant neutralizing epitopes and serves as an important antigen for the development of COVID-19 vaccines. Here, we showed that immunization of mice with a candidate subunit vaccine consisting of SARS-CoV-2 RBD and Fc fragment of human IgG, as an immunopotentiator, elicited high titer of RBD-specific antibodies with robust neutralizing activity against both pseudotyped and live SARS-CoV-2 infections. The mouse antisera could also effectively neutralize infection by pseudotyped SARS-CoV-2 with several natural mutations in RBD and the IgG extracted from the mouse antisera could also show neutralization against pseudotyped SARS-CoV and SARS-related coronavirus (SARSr-CoV). Vaccination of human ACE2 transgenic mice with RBD-Fc could effectively protect mice from the SARS-CoV-2 challenge. These results suggest that SARS-CoV-2 RBD-Fc has good potential to be further developed as an effective and broad-spectrum vaccine to prevent infection of the current SARS-CoV-2 and its mutants, as well as future emerging SARSr-CoVs and re-emerging SARS-CoV.

6.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-313429

ABSTRACT

Accumulating mutations on SARS-CoV-2 Spike (S) protein may increase the possibility of immune escape, challenging the present COVID-19 prophylaxis and clinical interventions. Here, in a panel of receptor binding domain (S-RBD) specific monoclonal antibodies (mAbs) with high neutralizing potency against authentic SARS-CoV-2, at least 6 of them were found to efficiently block the pseudovirus of 501Y.V2, a highly transmissible SARS-CoV-2 variant with escape mutations. The top 3 neutralizing Abs (13G9, 58G6 and 510A5) exhibited comparative ultrapotency as those being actively pursued for clinical development. Interestingly, the antigenic sites for the majority of our neutralizing Abs overlapped with a single epitope (13G9e) on S-RBD. Further, the 3-dimensional structures of 2 ultrapotent neutralizing Abs 13G9 or 58G6 in complex with SARS-CoV-2 S trimer demonstrated that both Abs bound to a steric region within S 472–490 . Moreover, a specific linear region (S 450–457 ) was identified as an additional target for 58G6. Importantly, our cryo-electron microscopy (cryo-EM) analysis revealed a unique phenomenon that the S-RBDs interacting with the fragments of antigen binding (Fabs) of 13G9 or 58G6 encoded by the IGHV1-58 and the IGKV3-20 gene segments were universally in the ‘up’ conformation in all observed particles. The potent neutralizing Abs presented in the current study may be promising candidates to fulfill the urgent needs for the current pandemic of SARS-CoV-2, and may of fundamental value for the next-generation vaccine development.

7.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-311951

ABSTRACT

After the epidemic of COVID-19, neutralizing antibodies (NAbs) against SARS-CoV-2 has been developed for the preventative and therapeutic purposes. However, few methodologies are reported in detail on how to rapidly and efficiently generate NAbs of interest. Here, we present a strategically optimized screening method for NAbs, which has enabled us to obtain SARS-CoV-2 receptor-binding domain (RBD) specific monoclonal Abs within 4 days, followed by additional 2 days to evaluate their neutralizing activities. Using this method, we obtained 198 specific Abs against SARS-CoV-2 RBD from the blood samples of COVID-19 convalescent patients, and 96 of them showed neutralizing activity. At least 20% of these NAbs exhibited high neutralizing potency. The top 2 NAbs showed the half-maximal inhibitory concentration (IC50) to block authentic SARS-CoV-2 at 9.88 and 11.13 ng/ml, respectively. Altogether, our study provides a fundamental methodology for discovering NAbs with potential preventative and therapeutic value for emerging infectious diseases.

8.
Environ Sci Pollut Res Int ; 29(27): 41534-41543, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1653699

ABSTRACT

The COVID-19 outbreak emerged in Wuhan, China, and was declared a global pandemic in March 2020. This study aimed to explore the association of daily mean temperature with the daily counts of COVID-19 cases in Beijing, Shanghai, Guangzhou, and Shenzhen, China. Data on daily confirmed cases of COVID-19 and daily mean temperatures were retrieved from the 4 first-tier cities in China. Distributed lag nonlinear models (DLNMs) were used to assess the association between daily mean temperature and the daily cases of COVID-19 during the study period. After controlling for the imported risk index and long-term trends, the distributed lag nonlinear model showed that there were nonlinear and lag relationships. The daily cumulative relative risk decreased for every 1.0 °C change in temperature in Shanghai, Guangzhou, and Shenzhen. However, the cumulative relative risk increased with a daily mean temperature below - 3 °C in Beijing and then decreased. Moreover, the delayed effects of lower temperatures mostly occurred within 6-7 days of exposure. There was a negative correlation between the cumulative relative risk of COVID-19 incidence and temperature, especially when the temperature was higher than - 3 °C. The conclusions from this paper will help government and health regulators in these cities take prevention and protection measures to address the COVID-19 crisis and the possible collapse of the health system in the future.


Subject(s)
COVID-19 , COVID-19/epidemiology , China/epidemiology , Cities/epidemiology , Humans , Incidence , Temperature , Time Factors
9.
Zhongguo Dang Dai Er Ke Za Zhi ; 23(11): 1091-1096, 2021 Nov 15.
Article in English, Chinese | MEDLINE | ID: covidwho-1513019

ABSTRACT

OBJECTIVES: To investigate vitamin D nutritional status in children after outbreak of coronavirus disease 2019 (COVID-19), as well as the effect of strict epidemic prevention and control measures for the COVID-19 epidemic on vitamin D nutritional status in children. METHODS: A total of 7 460 children who underwent routine physical examinations from February to August, 2020 and had normal results were retrospectively enrolled as the observation group, and 10 102 children who underwent routine physical examinations from February to August, 2019 (no epidemic of COVID-19) and had normal results were enrolled as the control group. The serum level of 25-hydroxy vitamin D [25(OH)D] was compared between the two groups. The children in the observation and control groups who underwent physical examinations in March and April were selected as the epidemic prevention subgroup (n=1 710) and non-epidemic subgroup (n=2 877) respectively. The subjects were divided into five age groups (infancy, early childhood, preschool, school age and adolescence), and serum 25(OH)D levels of children of all ages were compared between the epidemic prevention and non-epidemic subgroups. RESULTS: The observation group had a lower serum level of 25(OH)D than the control group in March and April (P<0.001). The epidemic prevention subgroup had a lower serum level of 25(OH)D than the non-epidemic subgroup in all age groups (P<0.001). The vitamin D sufficiency rate in early childhood, preschool, school and adolescent children from the epidemic prevention subgroup was lower than the non-epidemic subgroup (P<0.001), with a reduction of 10.71%, 18.76%, 59.63% and 56.29% respectively. CONCLUSIONS: Strict prevention and control measures for the COVID-19 epidemic may lead to a significant reduction in vitamin D level in children, especially school-aged and adolescent children. It is recommended to timely monitor vitamin D level in children, take vitamin D supplements, and increase the time of outdoor sunshine as far as possible under the premise of adherence to epidemic prevention regulations.


Subject(s)
COVID-19 , Vitamin D Deficiency , Adolescent , Child , Child, Preschool , Disease Outbreaks , Humans , Nutritional Status , Retrospective Studies , SARS-CoV-2 , Vitamin D , Vitamin D Deficiency/epidemiology
10.
Nat Commun ; 12(1): 6304, 2021 11 02.
Article in English | MEDLINE | ID: covidwho-1500462

ABSTRACT

Accumulating mutations in the SARS-CoV-2 Spike (S) protein can increase the possibility of immune escape, challenging the present COVID-19 prophylaxis and clinical interventions. Here, 3 receptor binding domain (RBD) specific monoclonal antibodies (mAbs), 58G6, 510A5 and 13G9, with high neutralizing potency blocking authentic SARS-CoV-2 virus display remarkable efficacy against authentic B.1.351 virus. Surprisingly, structural analysis has revealed that 58G6 and 13G9 both recognize the steric region S470-495 on the RBD, overlapping the E484K mutation presented in B.1.351. Also, 58G6 directly binds to another region S450-458 in the RBD. Significantly, 58G6 and 510A5 both demonstrate prophylactic efficacy against authentic SARS-CoV-2 and B.1.351 viruses in the transgenic mice expressing human ACE2 (hACE2), protecting weight loss and reducing virus loads. Together, we have evidenced 2 potent neutralizing Abs with unique mechanism targeting authentic SARS-CoV-2 mutants, which can be promising candidates to fulfill the urgent needs for the prolonged COVID-19 pandemic.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/prevention & control , SARS-CoV-2/immunology , Animals , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/administration & dosage , Antibodies, Neutralizing/chemistry , Antibodies, Viral/administration & dosage , Antibodies, Viral/chemistry , Binding Sites , COVID-19/pathology , COVID-19/virology , Epitopes , Humans , Mice , Mice, Transgenic , Mutation , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Viral Load/drug effects , Weight Loss/drug effects
11.
Theriogenology ; 177: 1-10, 2022 Jan 01.
Article in English | MEDLINE | ID: covidwho-1458733

ABSTRACT

Chloroquine (CQ) could function as a lysosomotropic agent to inhibit the endolysosomal trafficking in the autophagy pathway, and is widely used on malarial, tumor and recently COVID-19. However, the effect of CQ treatment on porcine immature Sertoli cells (iSCs) remains unclear. Here we showed that CQ could reduce iSC viability in a dose-dependent manner. CQ treatment (20 µM) on iSCs for 36h could elevate oxidative stress, damage mitochondrial function and promote apoptosis, which could be partially rescued by melatonin (MT) (10 nM). Transcriptome profiling identified 1611 differentially expressed genes (DEGs) (776 up- and 835 down-regulated) (20 µM CQ vs. DMSO), mainly involved in MAPK cascade, cell proliferation/apoptosis, HIF-1, PI3K-Akt and lysosome signaling pathways. In contrast, only 467 (224 up- and 243 down-regulated) DEGs (CQ + MT vs. DMSO) could be found after MT (10 nM) addition, enriched in cell cycle, regulation of apoptotic process, lysosome and reproduction pathways. Therefore, the partial rescue effects of MT on CQ treatment were confirmed by multiple assays (cell viability, ROS level, mitochondrial function, apoptosis, and mRNA levels of selected genes). Collectively, CQ treatment could impair porcine iSC viability by deranging the signaling pathways related to apoptosis and autophagy, which could be partially rescued by MT supplementation.


Subject(s)
COVID-19 , Melatonin , Swine Diseases , Animals , Apoptosis , Autophagy , COVID-19/drug therapy , COVID-19/veterinary , Chloroquine/pharmacology , Male , Melatonin/pharmacology , Phosphatidylinositol 3-Kinases , SARS-CoV-2 , Sertoli Cells , Swine
12.
Environ Sci Pollut Res Int ; 29(9): 13386-13395, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1446195

ABSTRACT

This study sought to identify the spatial, temporal, and spatiotemporal clusters of COVID-19 cases in 366 cities in mainland China with the highest risks and to explore the possible influencing factors of imported risks and environmental factors on the spatiotemporal aggregation, which would be useful to the design and implementation of critical preventative measures. The retrospective analysis of temporal, spatial, and spatiotemporal clustering of COVID-19 during the period (January 15 to February 25, 2020) was based on Kulldorff's time-space scanning statistics using the discrete Poisson probability model, and then the logistic regression model was used to evaluate the impact of imported risk and environmental factors on spatiotemporal aggregation. We found that the spatial distribution of COVID-19 cases was nonrandom; the Moran's I value ranged from 0.017 to 0.453 (P < 0.001). One most likely cluster and three secondary likely clusters were discovered in spatial cluster analysis. The period from February 2 to February 9, 2020, was identified as the most likely cluster in the temporal cluster analysis. One most likely cluster and seven secondary likely clusters were discovered in spatiotemporal cluster analysis. Imported risk, humidity, and inhalable particulate matter PM2.5 had a significant impact on temporal and spatial accumulation, and temperature and PM10 had a low correlation with the spatiotemporal aggregation of COVID-19. The information is useful for health departments to develop a better prevention strategy and potentially increase the effectiveness of public health interventions.


Subject(s)
COVID-19 , China , Cities , Cluster Analysis , Humans , Incidence , Retrospective Studies , SARS-CoV-2 , Spatio-Temporal Analysis
14.
Sci Bull (Beijing) ; 66(9): 925-936, 2021 May 15.
Article in English | MEDLINE | ID: covidwho-1386590

ABSTRACT

The SARS-CoV-2 infection is spreading rapidly worldwide. Efficacious antiviral therapeutics against SARS-CoV-2 is urgently needed. Here, we discovered that protoporphyrin IX (PpIX) and verteporfin, two Food and Drug Administration (FDA)-approved drugs, completely inhibited the cytopathic effect produced by SARS-CoV-2 infection at 1.25 µmol/L and 0.31 µmol/L, respectively, and their EC50 values of reduction of viral RNA were at nanomolar concentrations. The selectivity indices of PpIX and verteporfin were 952.74 and 368.93, respectively, suggesting a broad margin of safety. Importantly, PpIX and verteporfin prevented SARS-CoV-2 infection in mice adenovirally transduced with human angiotensin-converting enzyme 2 (ACE2). The compounds, sharing a porphyrin ring structure, were shown to bind viral receptor ACE2 and interfere with the interaction between ACE2 and the receptor-binding domain of viral S protein. Our study suggests that PpIX and verteporfin are potent antiviral agents against SARS-CoV-2 infection and sheds new light on developing novel chemoprophylaxis and chemotherapy against SARS-CoV-2.

15.
Medicine (Baltimore) ; 100(33): e26978, 2021 Aug 20.
Article in English | MEDLINE | ID: covidwho-1367078

ABSTRACT

BACKGROUND: The novel coronavirus disease 2019 (COVID-19) has changed people's way of life and posed great challenges to plastic surgery. Most of plastic surgeries are considered elective surgeries and are recommended to be delayed. But breast reconstruction in plastic surgery is special. Doctors' associations from different countries have different rules on whether breast reconstruction surgery should be delayed. For the controversial topic of immediate breast reconstruction in the COVID-19 pandemic, we conducted this study. METHODS: We searched English databases such as PubMed, Cochrane Library, and Embase. The publication time of papers was set to be from the establishment of the databases to February 2021. All studies on immediate breast reconstruction in the COVID-19 pandemic were included in our study. RESULTS: A total of 6 studies were included in this study. Four studies recommended the use of breast implants or tissue expansion for breast reconstruction surgery and had good results in their clinical practice. In addition, 1 study planned to use autologous free tissue transfer for breast reconstruction, and 1 study planned to use microsurgical techniques for breast reconstruction. But these 2 technologies are still in the planning stage and have not yet been implemented. CONCLUSIONS: In our opinion, breast cancer surgery belongs to confine operation, and breast reconstruction surgery should be performed immediately after the completion of breast cancer surgery. We recommend the use of breast implants for breast reconstruction surgery during the COVID-19 epidemic. Due to the limitations of the study, our proposed protocol for breast reconstruction surgery during the COVID-19 epidemic needs to be further validated in clinical studies.


Subject(s)
COVID-19/epidemiology , Mammaplasty , Pandemics , Time-to-Treatment , Adipose Tissue/transplantation , Breast Implants , Breast Neoplasms/surgery , Female , Humans , Mammaplasty/methods , Mastectomy , Microsurgery , SARS-CoV-2 , Tissue Expansion Devices , Transplantation, Autologous
16.
Signal Transduct Target Ther ; 6(1): 288, 2021 07 29.
Article in English | MEDLINE | ID: covidwho-1333906

ABSTRACT

The COVID-19 pandemic poses a global threat to public health and economy. The continuously emerging SARS-CoV-2 variants present a major challenge to the development of antiviral agents and vaccines. In this study, we identified that EK1 and cholesterol-coupled derivative of EK1, EK1C4, as pan-CoV fusion inhibitors, exhibit potent antiviral activity against SARS-CoV-2 infection in both lung- and intestine-derived cell lines (Calu-3 and Caco2, respectively). They are also effective against infection of pseudotyped SARS-CoV-2 variants B.1.1.7 (Alpha) and B.1.1.248 (Gamma) as well as those with mutations in S protein, including N417T, E484K, N501Y, and D614G, which are common in South African and Brazilian variants. Crystal structure revealed that EK1 targets the HR1 domain in the SARS-CoV-2 S protein to block virus-cell fusion and provide mechanistic insights into its broad and effective antiviral activity. Nasal administration of EK1 peptides to hACE2 transgenic mice significantly reduced viral titers in lung and intestinal tissues. EK1 showed good safety profiles in various animal models, supporting further clinical development of EK1-based pan-CoV fusion inhibitors against SARS-CoV-2 and its variants.


Subject(s)
Antiviral Agents , COVID-19/drug therapy , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Virus Internalization/drug effects , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Caco-2 Cells , Crystallography, X-Ray , Drug Evaluation, Preclinical , Humans , Mice, Transgenic , Protein Domains , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
17.
J Infect Public Health ; 14(9): 1127-1132, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1313254

ABSTRACT

OBJECTIVE: Currently, coronavirus disease 2019 (COVID-19) has spread worldwide and become a global health concern. Here, we report a familial cluster of six patients infected with severe acute respiratory coronavirus 2 (SARS-CoV-2) in a northern Chinese region and share our local experience with regard the control of COVID-19. METHODS: The demographic data, clinical features, laboratory examinations, and epidemiological characteristics of enrolled cases were collected and analyzed. Two family members (Cases 1 and 2) had Hubei exposure history and were admitted to the hospital with a confirmed diagnosis of COVID-19; eight familial members who had contact with them during the incubation period underwent quarantine in a hospital. We closely followed up all the family members and analyzed their clinical outcome. RESULTS: Case 3 had negative SARS-CoV-2 reverse transcription-polymerase chain reaction (RT-PCR) results but was suspected to have COVID-19 because of radiographic abnormalities. Cases 4 and 5 developed symptomatic COVID-19. Case 6 was considered an asymptomatic carrier as his SARS-CoV-2 RT-PCR result was positive. The other four family members with close contacts to COVID-19 patients had no evidence of SARS-CoV-2 infection. CONCLUSIONS: Our findings suggest that COVID-19 has infectivity during the incubation period and preventive quarantine is effective for controlling an outbreak of COVID-19 infection.


Subject(s)
COVID-19 , China/epidemiology , Disease Outbreaks , Humans , Quarantine , SARS-CoV-2
18.
Preprint in English | bioRxiv | ID: ppbiorxiv-449680

ABSTRACT

SARS-CoV-2 infection-induced hyper-inflammation links to the acute lung injury and COVID-19 severity. Identifying the primary mediators that initiate the uncontrolled hypercytokinemia is essential for treatments. Mast cells (MCs) are strategically located at the mucosa and beneficially or detrimentally regulate immune inflammations. Here we showed that SARS-CoV-2-triggeed MC degranulation initiated alveolar epithelial inflammation and lung injury. SARS-CoV-2 challenge induced MC degranulation in ACE-2 humanized mice and rhesus macaques, and a rapid MC degranulation could be recapitulated with Spike-RBD binding to ACE2 in cells; MC degranulation alterred various signaling pathways in alveolar epithelial cells, particularly, led to the production of pro-inflammatory factors and consequential disruption of tight junctions. Importantly, the administration of clinical MC stabilizers for blocking degranulation dampened SARS-CoV-2-induced production of pro-inflammatory factors and prevented lung injury. These findings uncover a novel mechanism for SARS-CoV-2 initiating lung inflammation, and suggest an off-label use of MC stabilizer as immunomodulators for COVID-19 treatments. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/449680v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@899996org.highwire.dtl.DTLVardef@1c26c0eorg.highwire.dtl.DTLVardef@1442cdcorg.highwire.dtl.DTLVardef@dd4204_HPS_FORMAT_FIGEXP M_FIG C_FIG In BriefSARS-CoV-2 triggers an immediate mast cell (MC) degranulation, which initiates the alveolar epithelial inflammation and disrupts the tight junction. MC stabilizers that block degranulation reduce virus-induced lung inflammation and injury. HighlightsO_LIThe binding of RBD of Spike protein of SARS-CoV-2-to ACE2 receptor protein triggers an immediate MC degranulation C_LIO_LIMC degranulation induces transcriptomic changes include an upregulated inflammatory signaling and a downregulated cell-junction signaling C_LIO_LIMC degranulation leads to alveolar epithelial inflammation and disruption of tight junctions C_LIO_LIMC stabilizer that inhibits degranulation reduces SARS-CoV-2-induced lung inflammation and injury in vivo C_LI

19.
Mediators Inflamm ; 2021: 6635925, 2021.
Article in English | MEDLINE | ID: covidwho-1175215

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was initially identified in China and currently worldwide dispersed, resulting in the coronavirus disease 2019 (COVID-19) pandemic. Notably, COVID-19 is characterized by systemic inflammation. However, the potential mechanisms of the "cytokine storm" of COVID-19 are still limited. In this study, fourteen peripheral blood samples from COVID-19 patients (n = 10) and healthy donors (n = 4) were collected to perform the whole-transcriptome sequencing. Lung tissues of COVID-19 patients (70%) presenting with ground-glass opacity. Also, the leukocytes and lymphocytes were significantly decreased in COVID-19 compared with the control group (p < 0.05). In total, 25,482 differentially expressed messenger RNAs (DE mRNA), 23 differentially expressed microRNAs (DE miRNA), and 410 differentially expressed long noncoding RNAs (DE lncRNAs) were identified in the COVID-19 samples compared to the healthy controls. Gene Ontology (GO) analysis showed that the upregulated DE mRNAs were mainly involved in antigen processing and presentation of endogenous antigen, positive regulation of T cell mediated cytotoxicity, and positive regulation of gamma-delta T cell activation. The downregulated DE mRNAs were mainly concentrated in the glycogen biosynthetic process. We also established the protein-protein interaction (PPI) networks of up/downregulated DE mRNAs and identified 4 modules. Functional enrichment analyses indicated that these module targets were associated with positive regulation of cytokine production, cytokine-mediated signaling pathway, leukocyte differentiation, and migration. A total of 6 hub genes were selected in the PPI module networks including AKT1, TNFRSF1B, FCGR2A, CXCL8, STAT3, and TLR2. Moreover, a competing endogenous RNA network showed the interactions between lncRNAs, mRNAs, and miRNAs. Our results highlight the potential pathogenesis of excessive cytokine production such as MSTRG.119845.30/hsa-miR-20a-5p/TNFRSF1B, MSTRG.119845.30/hsa-miR-29b-2-5p/FCGR2A, and MSTRG.106112.2/hsa-miR-6501-5p/STAT3 axis, which may also play an important role in the development of ground-glass opacity in COVID-19 patients. This study gives new insights into inflammation regulatory mechanisms of coding and noncoding RNAs in COVID-19, which may provide novel diagnostic biomarkers and therapeutic avenues for COVID-19 patients.


Subject(s)
COVID-19/blood , COVID-19/genetics , RNA/blood , RNA/genetics , SARS-CoV-2 , Adult , Aged , COVID-19/complications , Case-Control Studies , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/genetics , Cytokines/biosynthesis , Cytokines/genetics , Female , Gene Expression , Humans , Inflammation Mediators/blood , Male , MicroRNAs/blood , MicroRNAs/genetics , Middle Aged , Pandemics , Protein Interaction Maps/genetics , RNA, Long Noncoding/blood , RNA, Long Noncoding/genetics , RNA, Messenger/blood , RNA, Messenger/genetics , Sequence Analysis, RNA , Signal Transduction , Whole Exome Sequencing , Young Adult
20.
Front Immunol ; 12: 653189, 2021.
Article in English | MEDLINE | ID: covidwho-1172966

ABSTRACT

After the pandemic of COVID-19, neutralizing antibodies (NAbs) against SARS-CoV-2 have been developed for the prophylactic and therapeutic purposes. However, few methodologies are described in detail on how to rapidly and efficiently generate effective NAbs to SARS-CoV-2. Here, we integrated and optimized a strategically screening method for NAbs, which has enabled us to obtain SARS-CoV-2 receptor-binding domain (RBD) specific NAbs within 6 days, followed by additional 9 days for antibody production and function analysis. Using this method, we obtained 198 specific Abs against SARS-CoV-2 RBD from the blood samples of COVID-19 convalescent patients, and 96 of them showed neutralizing activity. At least 20% of these NAbs exhibited advanced neutralizing potency and high affinity, with the top two NAbs showing half-maximal inhibitory concentration (IC50) to block authentic SARS-CoV-2 at 9.88 and 11.13 ng/ml, respectively. Altogether, our study provides an effective methodology with high applicable value for discovering potential preventative and therapeutic NAbs for the emerging infectious diseases.


Subject(s)
Antibodies, Neutralizing , Antibodies, Viral , COVID-19 , SARS-CoV-2 , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , COVID-19/blood , COVID-19/immunology , Humans , SARS-CoV-2/immunology , SARS-CoV-2/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL