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1.
Signal Transduct Target Ther ; 7(1): 255, 2022 Jul 27.
Article in English | MEDLINE | ID: covidwho-1960331

ABSTRACT

SARS-CoV-2, the culprit pathogen of COVID-19, elicits prominent immune responses and cytokine storms. Intracellular Cl- is a crucial regulator of host defense, whereas the role of Cl- signaling pathway in modulating pulmonary inflammation associated with SARS-CoV-2 infection remains unclear. By using human respiratory epithelial cell lines, primary cultured human airway epithelial cells, and murine models of viral structural protein stimulation and SARS-CoV-2 direct challenge, we demonstrated that SARS-CoV-2 nucleocapsid (N) protein could interact with Smad3, which downregulated cystic fibrosis transmembrane conductance regulator (CFTR) expression via microRNA-145. The intracellular Cl- concentration ([Cl-]i) was raised, resulting in phosphorylation of serum glucocorticoid regulated kinase 1 (SGK1) and robust inflammatory responses. Inhibition or knockout of SGK1 abrogated the N protein-elicited airway inflammation. Moreover, N protein promoted a sustained elevation of [Cl-]i by depleting intracellular cAMP via upregulation of phosphodiesterase 4 (PDE4). Rolipram, a selective PDE4 inhibitor, countered airway inflammation by reducing [Cl-]i. Our findings suggested that Cl- acted as the crucial pathological second messenger mediating the inflammatory responses after SARS-CoV-2 infection. Targeting the Cl- signaling pathway might be a novel therapeutic strategy for COVID-19.


Subject(s)
COVID-19 , Chlorine/metabolism , MicroRNAs , Animals , COVID-19/genetics , Humans , Inflammation/pathology , Mice , MicroRNAs/metabolism , Nucleocapsid Proteins , Respiratory Mucosa/metabolism , Respiratory Mucosa/pathology , SARS-CoV-2
2.
Natl Sci Rev ; 9(3): nwac054, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1784379
3.
Am J Physiol Lung Cell Mol Physiol ; 322(5): L712-L721, 2022 05 01.
Article in English | MEDLINE | ID: covidwho-1759484

ABSTRACT

Accumulating evidence has confirmed that chronic obstructive pulmonary disease (COPD) is a risk factor for development of severe pathological changes in the peripheral lungs of patients with COVID-19. However, the underlying molecular mechanisms remain unclear. Because bronchiolar club cells are crucial for maintaining small airway homeostasis, we sought to explore whether the altered susceptibility to SARS-CoV-2 infection of the club cells might have contributed to the severe COVID-19 pneumonia in COPD patients. Our investigation on the quantity and distribution patterns of angiotensin-converting enzyme 2 (ACE2) in airway epithelium via immunofluorescence staining revealed that the mean fluorescence intensity of the ACE2-positive epithelial cells was significantly higher in club cells than those in other epithelial cells (including ciliated cells, basal cells, goblet cells, neuroendocrine cells, and alveolar type 2 cells). Compared with nonsmokers, the median percentage of club cells in bronchiolar epithelium and ACE2-positive club cells was significantly higher in COPD patients. In vitro, SARS-CoV-2 infection (at a multiplicity of infection of 1.0) of primary small airway epithelial cells, cultured on air-liquid interface, confirmed a higher percentage of infected ACE2-positive club cells in COPD patients than in nonsmokers. Our findings have indicated the role of club cells in modulating the pathogenesis of SARS-CoV-2-related severe pneumonia and the poor clinical outcomes, which may help physicians to formulate a novel therapeutic strategy for COVID-19 patients with coexisting COPD.


Subject(s)
COVID-19 , Pulmonary Disease, Chronic Obstructive , Angiotensin-Converting Enzyme 2 , Epithelial Cells , Humans , Lung , Peptidyl-Dipeptidase A , SARS-CoV-2
4.
Am J Chin Med ; 50(2): 351-369, 2022.
Article in English | MEDLINE | ID: covidwho-1723921

ABSTRACT

The development of anti-COVID-19 drugs has become the top priority since the outbreak of the epidemic, and Traditional Chinese medicine plays an important role in reducing mortality. Here, hesperidin and its glycosylation product, glucosyl hesperidin were selected to determine their antiviral activity against SARS-CoV-2 due to their structural specificity as reported. To be specific, their binding ability with ACE2, M, S, RBD and N proteins were verified with both in silico and wet lab methods, i.e., molecular docking and binding affinity tests, including biolayer interferometry assay (BLI) and isothermal titration calorimetry assay (ITC). Moreover, systematic pharmacological analysis was conducted to reveal their pharmacological mechanism in treating COVID-19. Finally, their antiviral activity against SARS-CoV-2 was determined in vitro in a biosafety level 3 (BSL3) laboratory. The results demonstrated their outstanding binding affinity with ACE2, M, S and RBD proteins, while showed barely unobserved binding with N protein, indicating their key roles in influencing the invasion and early replication phase of SARS-CoV-2. In addition, both hesperidin and glucosyl hesperidin were shown to have a great impact on immune, inflammation and virus infection induced by COVID-19 according to the systematic pharmacological analysis. Moreover, the IC50s of hesperidin and glucosyl hesperidin against SARS-CoV-2 were further determined (51.5 [Formula: see text]M and 5.5 mM, respectively) with cell-based in vitro assay, suggesting their great anti-SARS-CoV-2 activity. All in all, present research was the first to verify the binding ability of hesperidin and glucosyl hesperidin with SARS-CoV-2 proteins with both in silico and wet-lab methods and proposed the possibility of applying hesperidin and glucosyl hesperidin to treat COVID-19.


Subject(s)
COVID-19 , Hesperidin , Antiviral Agents/pharmacology , COVID-19/drug therapy , Computational Biology , Glucosides , Hesperidin/analogs & derivatives , Hesperidin/pharmacology , Humans , Molecular Docking Simulation , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism
5.
iScience ; 25(3): 103967, 2022 Mar 18.
Article in English | MEDLINE | ID: covidwho-1699805

ABSTRACT

The outbreak of Coronavirus disease 2019 (COVID-19) throughout the world has caused millions of death, while the dynamics of host responses and the underlying regulation mechanisms during SARS-CoV-2 infection are not well depicted. Lung tissues from a mouse model sensitized to SARS-CoV-2 infection were serially collected at different time points for evaluation of transcriptome, proteome, and phosphoproteome. We showed the ebb and flow of several host responses in the lung across the viral infection. The signaling pathways and kinases regulating networks were alternated at different phases of infection. This multiplex evaluation also revealed that many kinases of the CDK and MAPK family were interactive and served as functional hubs in mediating the signal transduction during SARS-CoV-2 infection. Our study not only revealed the dynamics of lung pathophysiology and their underlying molecular mechanisms during SARS-CoV-2 infection, but also highlighted some molecules and signaling pathways that might guide future investigations on COVID-19 therapies.

9.
N Engl J Med ; 382(18): 1708-1720, 2020 04 30.
Article in English | MEDLINE | ID: covidwho-1428982

ABSTRACT

BACKGROUND: Since December 2019, when coronavirus disease 2019 (Covid-19) emerged in Wuhan city and rapidly spread throughout China, data have been needed on the clinical characteristics of the affected patients. METHODS: We extracted data regarding 1099 patients with laboratory-confirmed Covid-19 from 552 hospitals in 30 provinces, autonomous regions, and municipalities in mainland China through January 29, 2020. The primary composite end point was admission to an intensive care unit (ICU), the use of mechanical ventilation, or death. RESULTS: The median age of the patients was 47 years; 41.9% of the patients were female. The primary composite end point occurred in 67 patients (6.1%), including 5.0% who were admitted to the ICU, 2.3% who underwent invasive mechanical ventilation, and 1.4% who died. Only 1.9% of the patients had a history of direct contact with wildlife. Among nonresidents of Wuhan, 72.3% had contact with residents of Wuhan, including 31.3% who had visited the city. The most common symptoms were fever (43.8% on admission and 88.7% during hospitalization) and cough (67.8%). Diarrhea was uncommon (3.8%). The median incubation period was 4 days (interquartile range, 2 to 7). On admission, ground-glass opacity was the most common radiologic finding on chest computed tomography (CT) (56.4%). No radiographic or CT abnormality was found in 157 of 877 patients (17.9%) with nonsevere disease and in 5 of 173 patients (2.9%) with severe disease. Lymphocytopenia was present in 83.2% of the patients on admission. CONCLUSIONS: During the first 2 months of the current outbreak, Covid-19 spread rapidly throughout China and caused varying degrees of illness. Patients often presented without fever, and many did not have abnormal radiologic findings. (Funded by the National Health Commission of China and others.).


Subject(s)
Betacoronavirus , Coronavirus Infections , Disease Outbreaks , Pandemics , Pneumonia, Viral , Adolescent , Adult , Aged , COVID-19 , Child , China/epidemiology , Coronavirus Infections/complications , Coronavirus Infections/diagnosis , Coronavirus Infections/epidemiology , Coronavirus Infections/therapy , Female , Fever/etiology , Humans , Male , Middle Aged , Patient Acuity , Pneumonia, Viral/complications , Pneumonia, Viral/diagnosis , Pneumonia, Viral/epidemiology , Pneumonia, Viral/therapy , SARS-CoV-2 , Young Adult
10.
Emerg Microbes Infect ; 10(1): 1751-1759, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1393119

ABSTRACT

The effectiveness of inactivated SARS-CoV-2 vaccines against the Delta variant, which has been associated with greater transmissibility and virulence, remains unclear. We conducted a test-negative case-control study to explore the vaccine effectiveness (VE) in real-world settings. We recruited participants aged 18-59 years who consisted of SARS-CoV-2 test-positive cases (n = 74) and test-negative controls (n = 292) during the outbreak of the Delta variant in May 2021 in Guangzhou city, China. Vaccination status was compared to estimate The VE of SARS-CoV-2 inactivated vaccines. A single dose of inactivated SARS-CoV-2 vaccine yielded the VE of only 13.8%. After adjusting for age and sex, the overall VE for two-dose vaccination was 59.0% (95% confidence interval: 16.0% to 81.6%) against coronavirus disease 2019 (COVID-19) and 70.2% (95% confidence interval: 29.6-89.3%) against moderate COVID-19 and 100% against severe COVID-19 which might be overestimated due to the small sample size. The VE of two-dose vaccination against COVID-19 reached 72.5% among participants aged 40-59 years, and was higher in females than in males against COVID-19 and moderate diseases. While single dose vaccination was not sufficiently protective, the two-dose dosing scheme of the inactivated vaccines was effective against the Delta variant infection in real-world settings, with the estimated efficacy exceeding the World Health Organization minimal threshold of 50%.


Subject(s)
COVID-19 Vaccines/standards , COVID-19/prevention & control , SARS-CoV-2/genetics , Adolescent , Adult , Age Distribution , COVID-19/classification , COVID-19 Vaccines/administration & dosage , Case-Control Studies , China , Disease Outbreaks , Female , Genetic Variation , Humans , Male , Middle Aged , Vaccines, Inactivated/administration & dosage , Vaccines, Inactivated/standards , Young Adult
11.
Ann Transl Med ; 9(11): 941, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1278842

ABSTRACT

BACKGROUND: Risk of adverse outcomes in COVID-19 patients by stratifying by the time from symptom onset to confirmed diagnosis status is still uncertain. METHODS: We included 1,590 hospitalized COVID-19 patients confirmed by real-time RT-PCR assay or high-throughput sequencing of pharyngeal and nasal swab specimens from 575 hospitals across China between 11 December 2019 and 31 January 2020. Times from symptom onset to confirmed diagnosis, from symptom onset to first medical visit and from first medical visit to confirmed diagnosis were described and turned into binary variables by the maximally selected rank statistics method. Then, survival analysis, including a log-rank test, Cox regression, and conditional inference tree (CTREE) was conducted, regarding whether patients progressed to a severe disease level during the observational period (assessed as severe pneumonia according to the Chinese Expert Consensus on Clinical Practice for Emergency Severe Pneumonia, admission to an intensive care unit, administration of invasive ventilation, or death) as the prognosis outcome, the dependent variable. Independent factors included whether the time from symptom onset to confirmed diagnosis was longer than 5 days (the exposure) and other demographic and clinical factors as multivariate adjustments. The clinical characteristics of the patients with different times from symptom onset to confirmed diagnosis were also compared. RESULTS: The medians of the times from symptom onset to confirmed diagnosis, from symptom onset to first medical visit, and from first medical visit to confirmed diagnosis were 6, 3, and 2 days. After adjusting for age, sex, smoking status, and comorbidity status, age [hazard ratio (HR): 1.03; 95% CI: 1.01-1.04], comorbidity (HR: 1.84; 95% CI: 1.23-2.73), and a duration from symptom onset to confirmed diagnosis of >5 days (HR: 1.69; 95% CI: 1.10-2.60) were independent predictors of COVID-19 prognosis, which echoed the CTREE models, with significant nodes such as time from symptom onset to confirmed diagnosis, age, and comorbidities. Males, older patients with symptoms such as dry cough/productive cough/shortness of breath, and prior COPD were observed more often in the patients who procrastinated before initiating the first medical consultation. CONCLUSIONS: A longer time from symptom onset to confirmed diagnosis yielded a worse COVID-19 prognosis.

12.
ERJ Open Res ; 7(2)2021 Apr.
Article in English | MEDLINE | ID: covidwho-1255901

ABSTRACT

This editorial reviews the evidence supporting benefits of pulmonary rehabilitation in #COVID19 patients, as well as some unanswered research questions https://bit.ly/39JY3SU.

13.
Arch Bronconeumol ; 58(1): 5-7, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1242878
14.
J Med Virol ; 93(5): 3257-3260, 2021 05.
Article in English | MEDLINE | ID: covidwho-1196531

ABSTRACT

Previous studies have revealed a diagnostic role of pathogen-specific IgA in respiratory infections. However, co-detection of serum specific IgA for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and common respiratory pathogens remains largely unexplored. This study utilizes a protein microarray technology for simultaneous and quantitative measurements of specific IgAs for eight different respiratory pathogens including adenovirus, respiratory syncytial virus, influenza virus type A, influenza virus type B, parainfluenza virus, mycoplasma pneumoniae, chlamydia pneumoniae, and SARS-CoV-2 in serum sample of patients with coronavirus disease 2019 (COVID-19). A total of 42 patients with COVID-19 were included and categorized into severe cases (20 cases) and nonsevere cases (22 cases). The results showed that co-detection rate of specific-IgA for SARS-CoV-2 with at least one pathogen were significantly higher in severe cases than that of nonsevere cases (72.2% vs. 46.2%, p = .014). Our study indicates that co-detection of IgA antibodies for respiratory pathogens might provide diagnostic value for the clinics and also be informative for risk stratification and disease management in patients with COVID-19.


Subject(s)
Antibodies, Viral/blood , COVID-19/immunology , Immunoglobulin A/blood , SARS-CoV-2/immunology , Adult , Antibody Specificity , COVID-19/pathology , Female , Humans , Male , Middle Aged
15.
J Allergy Clin Immunol Pract ; 9(7): 2645-2655.e14, 2021 07.
Article in English | MEDLINE | ID: covidwho-1118526

ABSTRACT

BACKGROUND: Chronic respiratory diseases (CRD) are common among patients with coronavirus disease 2019 (COVID-19). OBJECTIVES: We sought to determine the association between CRD (including disease overlap) and the clinical outcomes of COVID-19. METHODS: Data of diagnoses, comorbidities, medications, laboratory results, and clinical outcomes were extracted from the national COVID-19 reporting system. CRD was diagnosed based on International Classification of Diseases-10 codes. The primary endpoint was the composite outcome of needing invasive ventilation, admission to intensive care unit, or death within 30 days after hospitalization. The secondary endpoint was death within 30 days after hospitalization. RESULTS: We included 39,420 laboratory-confirmed patients from the electronic medical records as of May 6, 2020. Any CRD and CRD overlap was present in 2.8% and 0.2% of patients, respectively. Chronic obstructive pulmonary disease (COPD) was most common (56.6%), followed by bronchiectasis (27.9%) and asthma (21.7%). COPD-bronchiectasis overlap was the most common combination (50.7%), followed by COPD-asthma (36.2%) and asthma-bronchiectasis overlap (15.9%). After adjustment for age, sex, and other systemic comorbidities, patients with COPD (odds ratio [OR]: 1.71, 95% confidence interval [CI]: 1.44-2.03) and asthma (OR: 1.45, 95% CI: 1.05-1.98), but not bronchiectasis, were more likely to reach to the composite endpoint compared with those without at day 30 after hospitalization. Patients with CRD were not associated with a greater likelihood of dying from COVID-19 compared with those without. Patients with CRD overlap did not have a greater risk of reaching the composite endpoint compared with those without. CONCLUSION: CRD was associated with the risk of reaching the composite endpoint, but not death, of COVID-19.


Subject(s)
Asthma , COVID-19 , Pulmonary Disease, Chronic Obstructive , Asthma/epidemiology , Comorbidity , Hospitalization , Humans , Pulmonary Disease, Chronic Obstructive/epidemiology , Retrospective Studies , Risk Factors , SARS-CoV-2
16.
J Med Virol ; 93(5): 3257-3260, 2021 05.
Article in English | MEDLINE | ID: covidwho-1051317

ABSTRACT

Previous studies have revealed a diagnostic role of pathogen-specific IgA in respiratory infections. However, co-detection of serum specific IgA for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and common respiratory pathogens remains largely unexplored. This study utilizes a protein microarray technology for simultaneous and quantitative measurements of specific IgAs for eight different respiratory pathogens including adenovirus, respiratory syncytial virus, influenza virus type A, influenza virus type B, parainfluenza virus, mycoplasma pneumoniae, chlamydia pneumoniae, and SARS-CoV-2 in serum sample of patients with coronavirus disease 2019 (COVID-19). A total of 42 patients with COVID-19 were included and categorized into severe cases (20 cases) and nonsevere cases (22 cases). The results showed that co-detection rate of specific-IgA for SARS-CoV-2 with at least one pathogen were significantly higher in severe cases than that of nonsevere cases (72.2% vs. 46.2%, p = .014). Our study indicates that co-detection of IgA antibodies for respiratory pathogens might provide diagnostic value for the clinics and also be informative for risk stratification and disease management in patients with COVID-19.


Subject(s)
Antibodies, Viral/blood , COVID-19/immunology , Immunoglobulin A/blood , SARS-CoV-2/immunology , Adult , Antibody Specificity , COVID-19/pathology , Female , Humans , Male , Middle Aged
17.
ACS Nano ; 15(2): 2738-2752, 2021 02 23.
Article in English | MEDLINE | ID: covidwho-1036015

ABSTRACT

The coronavirus disease pandemic of 2019 (COVID-19) caused by the novel SARS-CoV-2 coronavirus resulted in economic losses and threatened human health worldwide. The pandemic highlights an urgent need for a stable, easily produced, and effective vaccine. SARS-CoV-2 uses the spike protein receptor-binding domain (RBD) to bind its cognate receptor, angiotensin-converting enzyme 2 (ACE2), and initiate membrane fusion. Thus, the RBD is an ideal target for vaccine development. In this study, we designed three different RBD-conjugated nanoparticle vaccine candidates, namely, RBD-Ferritin (24-mer), RBD-mi3 (60-mer), and RBD-I53-50 (120-mer), via covalent conjugation using the SpyTag-SpyCatcher system. When mice were immunized with the RBD-conjugated nanoparticles (NPs) in conjunction with the AddaVax or Sigma Adjuvant System, the resulting antisera exhibited 8- to 120-fold greater neutralizing activity against both a pseudovirus and the authentic virus than those of mice immunized with monomeric RBD. Most importantly, sera from mice immunized with RBD-conjugated NPs more efficiently blocked the binding of RBD to ACE2 in vitro, further corroborating the promising immunization effect. Additionally, the vaccine has distinct advantages in terms of a relatively simple scale-up and flexible assembly. These results illustrate that the SARS-CoV-2 RBD-conjugated nanoparticles developed in this study are a competitive vaccine candidate and that the carrier nanoparticles could be adopted as a universal platform for a future vaccine development.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19 Vaccines/therapeutic use , COVID-19/prevention & control , Nanoparticles/therapeutic use , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/metabolism , Animals , COVID-19/metabolism , COVID-19 Vaccines/pharmacology , Chlorocebus aethiops , Female , HEK293 Cells , Host-Pathogen Interactions , Humans , Mice , Mice, Inbred BALB C , Models, Molecular , Protein Binding , Protein Interaction Domains and Motifs , Spike Glycoprotein, Coronavirus/chemistry , Vero Cells
18.
Respirology ; 25(6): 657-658, 2020 06.
Article in English | MEDLINE | ID: covidwho-887934
20.
Lancet Reg Health West Pac ; 6: 100073, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-970260
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