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1.
Cell Mol Immunol ; 18(6): 1602-1604, 2021 06.
Article in English | MEDLINE | ID: covidwho-1223085
2.
J Biomed Res ; 35(3): 216-227, 2021 Jan 29.
Article in English | MEDLINE | ID: covidwho-1219565

ABSTRACT

The outbreak of COVID-19 caused by SARS-CoV-2 is spreading worldwide, with the pathogenesis mostly unclear. Both virus and host-derived microRNA (miRNA) play essential roles in the pathology of virus infection. This study aims to uncover the mechanism for SARS-CoV-2 pathogenicity from the perspective of miRNA. We scanned the SARS-CoV-2 genome for putative miRNA genes and miRNA targets and conducted in vivo experiments to validate the virus-encoded miRNAs and their regulatory role on the putative targets. One of such virus-encoded miRNAs, MR147-3p, was overexpressed that resulted in significantly decreased transcript levels of all of the predicted targets in human, i.e., EXOC7, RAD9A, and TFE3 in the virus-infected cells. The analysis showed that the immune response and cytoskeleton organization are two of the most notable biological processes regulated by the infection-modulated miRNAs. Additionally, the genomic mutation of SARS-CoV-2 contributed to the changed miRNA repository and targets, suggesting a possible role of miRNAs in the attenuated phenotype of SARS-CoV-2 during its evolution. This study provided a comprehensive view of the miRNA-involved regulatory system during SARS-CoV-2 infection, indicating possible antiviral therapeutics against SARS-CoV-2 through intervening miRNA regulation.

3.
Signal Transduct Target Ther ; 6(1): 165, 2021 04 24.
Article in English | MEDLINE | ID: covidwho-1199266

ABSTRACT

The global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires an urgent need to find effective therapeutics for the treatment of coronavirus disease 2019 (COVID-19). In this study, we developed an integrative drug repositioning framework, which fully takes advantage of machine learning and statistical analysis approaches to systematically integrate and mine large-scale knowledge graph, literature and transcriptome data to discover the potential drug candidates against SARS-CoV-2. Our in silico screening followed by wet-lab validation indicated that a poly-ADP-ribose polymerase 1 (PARP1) inhibitor, CVL218, currently in Phase I clinical trial, may be repurposed to treat COVID-19. Our in vitro assays revealed that CVL218 can exhibit effective inhibitory activity against SARS-CoV-2 replication without obvious cytopathic effect. In addition, we showed that CVL218 can interact with the nucleocapsid (N) protein of SARS-CoV-2 and is able to suppress the LPS-induced production of several inflammatory cytokines that are highly relevant to the prevention of immunopathology induced by SARS-CoV-2 infection.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/metabolism , Computer Simulation , Drug Repositioning , Models, Biological , SARS-CoV-2/metabolism , Humans
5.
J Virol ; 95(4)2021 01 28.
Article in English | MEDLINE | ID: covidwho-1054610

ABSTRACT

Among seven coronaviruses that infect humans, three (severe acute respiratory syndrome coronavirus [SARS-CoV], Middle East respiratory syndrome coronavirus [MERS-CoV], and the newly identified severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) are associated with a severe, life-threatening respiratory infection and multiorgan failure. We previously proposed that the cationically modified chitosan N-(2-hydroxypropyl)-3-trimethylammonium chitosan chloride (HTCC) is a potent inhibitor of human coronavirus NL63 (HCoV-NL63). Next, we demonstrated the broad-spectrum antiviral activity of the compound, as it inhibited all low-pathogenicity human coronaviruses (HCoV-NL63, HCoV-229E, HCoV-OC43, and HCoV-HKU1). Here, using in vitro and ex vivo models of human airway epithelia, we show that HTCC effectively blocks MERS-CoV and SARS-CoV-2 infection. We also confirmed the mechanism of action for these two viruses, showing that the polymer blocks the virus entry into the host cell by interaction with the S protein.IMPORTANCE The beginning of 2020 brought us information about the novel coronavirus emerging in China. Rapid research resulted in the characterization of the pathogen, which appeared to be a member of the SARS-like cluster, commonly seen in bats. Despite the global and local efforts, the virus escaped the health care measures and rapidly spread in China and later globally, officially causing a pandemic and global crisis in March 2020. At present, different scenarios are being written to contain the virus, but the development of novel anticoronavirals for all highly pathogenic coronaviruses remains the major challenge. Here, we describe the antiviral activity of an HTCC compound, previously developed by us, which may be used as a potential inhibitor of currently circulating highly pathogenic coronaviruses-SARS-CoV-2 and MERS-CoV.


Subject(s)
COVID-19/drug therapy , Chitosan/analogs & derivatives , Coronavirus Infections/drug therapy , Middle East Respiratory Syndrome Coronavirus/drug effects , Quaternary Ammonium Compounds/pharmacology , SARS-CoV-2/drug effects , Antiviral Agents/pharmacology , COVID-19/epidemiology , COVID-19/virology , Chitosan/pharmacology , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Humans , Middle East Respiratory Syndrome Coronavirus/metabolism , Middle East Respiratory Syndrome Coronavirus/physiology , Pandemics , Respiratory Mucosa/drug effects , Respiratory Mucosa/virology , SARS-CoV-2/metabolism , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization/drug effects
6.
J Infect Dis ; 222(5): 746-754, 2020 08 04.
Article in English | MEDLINE | ID: covidwho-990712

ABSTRACT

Coronavirus disease 2019 (COVID-19) is an emerging infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We investigated the serum cytokine and chemokine levels in asymptomatic, mild, moderate, severe, and convalescent SARS-CoV-2-infected cases. Proinflammatory cytokine and chemokine production induced by SARS-CoV-2 were observed not only in symptomatic patients but also in asymptomatic cases, and returned to normal after recovery. IL-6, IL-7, IL-10, IL-18, G-CSF, M-CSF, MCP-1, MCP-3, IP-10, MIG, and MIP-1α were found to be associated with the severity of COVID-19. Moreover, a set of cytokine and chemokine profiles were significantly higher in SARS-CoV-2-infected male than female patients. The serum levels of MCP-1, G-CSF, and VEGF were weakly and positively correlated with viral titers. We suggest that combinatorial analysis of serum cytokines and chemokines with clinical classification may contribute to evaluation of the severity of COVID-19 and optimize the therapeutic strategies.


Subject(s)
Chemokines/blood , Coronavirus Infections/blood , Cytokines/blood , Pneumonia, Viral/blood , Adult , Betacoronavirus/isolation & purification , COVID-19 , Chemokine CCL2/blood , Coronavirus Infections/diagnosis , Coronavirus Infections/immunology , Coronavirus Infections/virology , Female , Granulocyte Colony-Stimulating Factor/blood , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , SARS-CoV-2 , Severity of Illness Index , Vascular Endothelial Growth Factor A/blood , Viral Load
7.
Virology ; 549: 1-4, 2020 10.
Article in English | MEDLINE | ID: covidwho-684730

ABSTRACT

The current outbreak of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was reported in China firstly. A rapid, highly sensitive, specific, and simple operational method was needed for the detection of SARS-CoV-2. Here, we established a real-time reverse-transcription recombinase-aided amplification assay (RT-RAA) to detect SARS-CoV-2 rapidly. The primers and probe were designed based on the nucleocapsid protein gene (N gene) sequence of SARS-CoV-2. The detection limit was 10 copies per reaction in this assay, which could be conducted within 15 min at a constant temperature (39 °C), without any cross-reactions with other respiratory tract pathogens, such as other coronaviruses. Furthermore, compared with commercial real-time RT-PCR assay, it showed a kappa value of 0.959 (p < 0.001) from 150 clinical specimens. These results indicated that this real-time RT-RAA assay may be a valuable tool for detecting SARS-CoV-2.


Subject(s)
Betacoronavirus/genetics , Clinical Laboratory Techniques/methods , Coronavirus Infections/virology , Genes, Viral , Nucleic Acid Amplification Techniques/methods , Nucleocapsid Proteins/genetics , Pneumonia, Viral/virology , Betacoronavirus/isolation & purification , COVID-19 , COVID-19 Testing , COVID-19 Vaccines , China/epidemiology , Clinical Laboratory Techniques/statistics & numerical data , Coronavirus Infections/diagnosis , Coronavirus Infections/epidemiology , Coronavirus Nucleocapsid Proteins , Humans , Limit of Detection , Nucleic Acid Amplification Techniques/statistics & numerical data , Pandemics , Phosphoproteins , Pneumonia, Viral/diagnosis , Pneumonia, Viral/epidemiology , RNA, Viral/analysis , RNA, Viral/genetics , Real-Time Polymerase Chain Reaction/methods , Real-Time Polymerase Chain Reaction/statistics & numerical data , Recombinases , Reverse Transcriptase Polymerase Chain Reaction/methods , Reverse Transcriptase Polymerase Chain Reaction/statistics & numerical data , SARS-CoV-2 , Sensitivity and Specificity
8.
Virus Res ; 285: 198005, 2020 08.
Article in English | MEDLINE | ID: covidwho-261608

ABSTRACT

Accumulating evidence shows that microbial co-infection increases the risk of disease severity in humans. There have been few studies about SARS-CoV-2 co-infection with other pathogens. In this retrospective study, 257 laboratory-confirmed COVID-19 patients in Jiangsu Province were enrolled from January 22 to February 2, 2020. They were re-confirmed by real-time RT-PCR and tested for 39 respiratory pathogens. In total, 24 respiratory pathogens were found among the patients, and 242 (94.2 %) patients were co-infected with one or more pathogens. Bacterial co-infections were dominant in all COVID-19 patients, Streptococcus pneumoniae was the most common, followed by Klebsiella pneumoniae and Haemophilus influenzae. The highest and lowest rates of co-infections were found in patients aged 15-44 and below 15, respectively. Most co-infections occurred within 1-4 days of onset of COVID-19 disease. In addition, the proportion of viral co-infections, fungal co-infections and bacterial-fungal co-infections were the highest severe COVID-19 cases. These results will provide a helpful reference for diagnosis and clinical treatment of COVID-19 patients.


Subject(s)
Bacterial Infections/complications , Betacoronavirus , Coinfection , Coronavirus Infections/complications , Mycoses/complications , Pneumonia, Viral/complications , Virus Diseases/complications , Adolescent , Adult , Age Factors , Aged , COVID-19 , Female , Humans , Male , Middle Aged , Pandemics , Retrospective Studies , SARS-CoV-2 , Time Factors , Young Adult
9.
Virology ; 546: 122-126, 2020 07.
Article in English | MEDLINE | ID: covidwho-186247

ABSTRACT

Since SARS-CoV-2 spreads rapidly around the world, data have been needed on the natural fluctuation of viral load and clinical indicators associated with it. We measured and compared viral loads of SARS-CoV-2 from pharyngeal swab, IgM anti-SARS-CoV-2, CRP and SAA from serum of 114 COVID-19 patients on admission. Positive rates of IgM anti-SARS-CoV-2, CRP and SAA were 80.7%, 36% and 75.4% respectively. Among IgM-positive patients, viral loads showed different trends among cases with different severity, While viral loads of IgM-negative patients tended to increase along with the time after onset. As the worsening of severity, the positive rates of CRP and SAA also showed trends of increase. Different CRP/SAA type showed associations with viral loads in patients in different severity and different time after onset. Combination of the IgM and CRP/SAA with time after onset and severity may give suggestions on the viral load and condition judgment of COVID-19 patients.


Subject(s)
Antibodies, Viral/blood , Coronavirus Infections/diagnosis , Immunoglobulin M/blood , Pneumonia, Viral/diagnosis , Viral Load , Adolescent , Adult , Aged , Betacoronavirus , Biomarkers/blood , C-Reactive Protein/analysis , COVID-19 , Child , Coronavirus Infections/blood , Female , Humans , Male , Middle Aged , Pandemics , Pharynx/virology , Pneumonia, Viral/blood , SARS-CoV-2 , Serum Amyloid A Protein/analysis , Young Adult
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