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1.
Nature ; 603(7899): 145-151, 2022 03.
Article in English | MEDLINE | ID: covidwho-1631700

ABSTRACT

COVID-19, which is caused by infection with SARS-CoV-2, is characterized by lung pathology and extrapulmonary complications1,2. Type I interferons (IFNs) have an essential role in the pathogenesis of COVID-19 (refs 3-5). Although rapid induction of type I IFNs limits virus propagation, a sustained increase in the levels of type I IFNs in the late phase of the infection is associated with aberrant inflammation and poor clinical outcome5-17. Here we show that the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which controls immunity to cytosolic DNA, is a critical driver of aberrant type I IFN responses in COVID-19 (ref. 18). Profiling COVID-19 skin manifestations, we uncover a STING-dependent type I IFN signature that is primarily mediated by macrophages adjacent to areas of endothelial cell damage. Moreover, cGAS-STING activity was detected in lung samples from patients with COVID-19 with prominent tissue destruction, and was associated with type I IFN responses. A lung-on-chip model revealed that, in addition to macrophages, infection with SARS-CoV-2 activates cGAS-STING signalling in endothelial cells through mitochondrial DNA release, which leads to cell death and type I IFN production. In mice, pharmacological inhibition of STING reduces severe lung inflammation induced by SARS-CoV-2 and improves disease outcome. Collectively, our study establishes a mechanistic basis of pathological type I IFN responses in COVID-19 and reveals a principle for the development of host-directed therapeutics.


Subject(s)
COVID-19/immunology , COVID-19/pathology , Interferon Type I/immunology , Membrane Proteins/metabolism , Nucleotidyltransferases/metabolism , SARS-CoV-2/immunology , Animals , COVID-19/metabolism , COVID-19/virology , Cells, Cultured , DNA, Mitochondrial/metabolism , Disease Models, Animal , Disease Progression , Endothelial Cells/pathology , Female , Gene Expression Regulation/immunology , Humans , Immunity, Innate , Lung/immunology , Lung/metabolism , Lung/pathology , Lung/virology , Macrophages/immunology , Membrane Proteins/antagonists & inhibitors , Mice , Mice, Inbred C57BL , Pneumonia/immunology , Pneumonia/metabolism , Pneumonia/pathology , Pneumonia/virology , SARS-CoV-2/pathogenicity , Signal Transduction , Skin/immunology , Skin/metabolism , Skin/pathology
2.
Int J Mol Sci ; 22(23)2021 Nov 27.
Article in English | MEDLINE | ID: covidwho-1560687

ABSTRACT

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe respiratory disorders that are caused by aspiration, sepsis, trauma, and pneumonia. A clinical feature of ALI/ARDS is the acute onset of severe hypoxemia, and the mortality rate, which is estimated at 38-50%, remains high. Although prostaglandins (PGs) are detected in the bronchoalveolar lavage fluid of patients with ALI/ARDS, the role of PGF2α in ALI remains unclear. We aimed to clarify the role of PGF2α/PGF2α receptor (FP) signaling in acid-induced ALI using an FP receptor antagonist, AL8810. Intratracheal injection of hydrochloric acid (HCl) increased neutrophil migration into the lungs, leading to respiratory dysfunction. Pre-administration of AL8810 further increased these features. Moreover, pre-treatment with AL8810 enhanced the HCl-induced expression of pro-inflammatory cytokines and neutrophil migratory factors in the lungs. Administration of HCl decreased the gene expression of lung surfactant proteins, which was further reduced by co-administration of AL8810. Administration of AL8810 also increased lung edema and reduced mRNA expression of epithelial sodium channel in the lungs, indicating that AL8810 reduced fluid clearance. Furthermore, AL8810 also increased lipopolysaccharide-induced expression of adhesion molecules such as intracellular adhesion molecule-1 and E-selectin in human umbilical vein endothelial cells. These results indicate that inhibition of FP receptors by AL8810 exacerbated HCl-induced ALI.


Subject(s)
Acute Lung Injury/metabolism , Lung/drug effects , Pneumonia/metabolism , Receptors, Prostaglandin/antagonists & inhibitors , Respiratory Distress Syndrome/metabolism , Acute Lung Injury/chemically induced , Acute Lung Injury/pathology , Animals , Disease Models, Animal , Female , Hydrochloric Acid/toxicity , Lung/metabolism , Lung/pathology , Mice , Mice, Inbred C57BL , Pneumonia/chemically induced , Pneumonia/immunology , Pneumonia/pathology , Prostaglandins F/metabolism , Respiratory Distress Syndrome/chemically induced , Respiratory Distress Syndrome/pathology
3.
Dis Markers ; 2021: 6803510, 2021.
Article in English | MEDLINE | ID: covidwho-1443673

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently the most significant public health threat worldwide. Patients with severe COVID-19 usually have pneumonia concomitant with local inflammation and sometimes a cytokine storm. Specific components of the SARS-CoV-2 virus trigger lung inflammation, and recruitment of immune cells to the lungs exacerbates this process, although much remains unknown about the pathogenesis of COVID-19. Our study of lung type II pneumocyte cells (A549) demonstrated that ORF7, an open reading frame (ORF) in the genome of SARS-CoV-2, induced the production of CCL2, a chemokine that promotes the chemotaxis of monocytes, and decreased the expression of IL-8, a chemokine that recruits neutrophils. A549 cells also had an increased level of IL-6. The results of our chemotaxis Transwell assay suggested that ORF7 augmented monocyte infiltration and reduced the number of neutrophils. We conclude that the ORF7 of SARS-CoV-2 may have specific effects on the immunological changes in tissues after infection. These results suggest that the functions of other ORFs of SARS-CoV-2 should also be comprehensively examined.


Subject(s)
COVID-19/metabolism , Chemotaxis , Monocytes/pathology , Neutrophils/pathology , Open Reading Frames/physiology , Pneumonia/pathology , Viral Proteins/metabolism , A549 Cells , Chemokine CCL2/metabolism , Humans , In Vitro Techniques , Monocytes/immunology , Monocytes/metabolism , Neutrophils/immunology , Neutrophils/metabolism , Pneumonia/immunology , Pneumonia/metabolism , SARS-CoV-2/metabolism , Viral Proteins/genetics
4.
Respir Res ; 21(1): 154, 2020 Jun 18.
Article in English | MEDLINE | ID: covidwho-1331943

ABSTRACT

Electronic cigarette (e-cig) vaping is increasing rapidly in the United States, as e-cigs are considered less harmful than combustible cigarettes. However, limited research has been conducted to understand the possible mechanisms that mediate toxicity and pulmonary health effects of e-cigs. We hypothesized that sub-chronic e-cig exposure induces inflammatory response and dysregulated repair/extracellular matrix (ECM) remodeling, which occur through the α7 nicotinic acetylcholine receptor (nAChRα7). Adult wild-type (WT), nAChRα7 knockout (KO), and lung epithelial cell-specific KO (nAChRα7 CreCC10) mice were exposed to e-cig aerosol containing propylene glycol (PG) with or without nicotine. Bronchoalveolar lavage fluids (BALF) and lung tissues were collected to determine e-cig induced inflammatory response and ECM remodeling, respectively. Sub-chronic e-cig exposure with nicotine increased inflammatory cellular influx of macrophages and T-lymphocytes including increased pro-inflammatory cytokines in BALF and increased SARS-Cov-2 Covid-19 ACE2 receptor, whereas nAChRα7 KO mice show reduced inflammatory responses associated with decreased ACE2 receptor. Interestingly, matrix metalloproteinases (MMPs), such as MMP2, MMP8 and MMP9, were altered both at the protein and mRNA transcript levels in female and male KO mice, but WT mice exposed to PG alone showed a sex-dependent phenotype. Moreover, MMP12 was increased significantly in male mice exposed to PG with or without nicotine in a nAChRα7-dependent manner. Additionally, sub-chronic e-cig exposure with or without nicotine altered the abundance of ECM proteins, such as collagen and fibronectin, significantly in a sex-dependent manner, but without the direct role of nAChRα7 gene. Overall, sub-chronic e-cig exposure with or without nicotine affected lung inflammation and repair responses/ECM remodeling, which were mediated by nAChRα7 in a sex-dependent manner.


Subject(s)
Coronavirus Infections/epidemiology , Electronic Nicotine Delivery Systems , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/epidemiology , Pneumonia/metabolism , Vaping/adverse effects , alpha7 Nicotinic Acetylcholine Receptor/genetics , Angiotensin-Converting Enzyme 2 , Animals , Blood Gas Analysis , Blotting, Western , Bronchoalveolar Lavage Fluid , COVID-19 , Cytokines/analysis , Disease Models, Animal , Female , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Pandemics , Pneumonia/physiopathology , Random Allocation , Reference Values , Role , Severe Acute Respiratory Syndrome/epidemiology , Signal Transduction/genetics
5.
Cells ; 10(7)2021 07 01.
Article in English | MEDLINE | ID: covidwho-1323124

ABSTRACT

Activation of Transient Receptor Potential (TRP) channels can disrupt endothelial barrier function, as their mediated Ca2+ influx activates the CaM (calmodulin)/MLCK (myosin light chain kinase)-signaling pathway, and thereby rearranges the cytoskeleton, increases endothelial permeability and thus can facilitate activation of inflammatory cells and formation of pulmonary edema. Interestingly, TRP channel subunits can build heterotetramers, whereas heteromeric TRPC1/4, TRPC3/6 and TRPV1/4 are expressed in the lung endothelium and could be targeted as a protective strategy to reduce endothelial permeability in pulmonary inflammation. An update on TRP heteromers and their role in lung inflammation will be provided with this review.


Subject(s)
Pneumonia/metabolism , Protein Multimerization , Transient Receptor Potential Channels/metabolism , Animals , Endothelial Cells/metabolism , Endothelial Cells/pathology , Humans , Ion Channel Gating , Models, Biological , Pneumonia/pathology , Pneumonia/physiopathology
6.
Pharmacol Res ; 157: 104820, 2020 07.
Article in English | MEDLINE | ID: covidwho-1318923

ABSTRACT

The Coronavirus Disease 2019 (COVID-19) pandemic has become a huge threaten to global health, which raise urgent demand of developing efficient therapeutic strategy. The aim of the present study is to dissect the chemical composition and the pharmacological mechanism of Qingfei Paidu Decoction (QFPD), a clinically used Chinese medicine for treating COVID-19 patients in China. Through comprehensive analysis by liquid chromatography coupled with high resolution mass spectrometry (MS), a total of 129 compounds of QFPD were putatively identified. We also constructed molecular networking of mass spectrometry data to classify these compounds into 14 main clusters, in which exhibited specific patterns of flavonoids (45 %), glycosides (15 %), carboxylic acids (10 %), and saponins (5 %). The target network model of QFPD, established by predicting and collecting the targets of identified compounds, indicated a pivotal role of Ma Xing Shi Gan Decoction (MXSG) in the therapeutic efficacy of QFPD. Supportively, through transcriptomic analysis of gene expression after MXSG administration in rat model of LPS-induced pneumonia, the thrombin and Toll-like receptor (TLR) signaling pathway were suggested to be essential pathways for MXSG mediated anti-inflammatory effects. Besides, changes in content of major compounds in MXSG during decoction were found by the chemical analysis. We also validate that one major compound in MXSG, i.e. glycyrrhizic acid, inhibited TLR agonists induced IL-6 production in macrophage. In conclusion, the integration of in silico and experimental results indicated that the therapeutic effects of QFPD against COVID-19 may be attributed to the anti-inflammatory effects of MXSG, which supports the rationality of the compatibility of TCM.


Subject(s)
Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Drugs, Chinese Herbal/analysis , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic use , Pneumonia, Viral/drug therapy , Animals , Anti-Inflammatory Agents/analysis , Anti-Inflammatory Agents/pharmacology , COVID-19 , Cells, Cultured , Computer Simulation , Coronavirus Infections/genetics , Gene Expression/drug effects , Glycyrrhizic Acid/pharmacology , Humans , Interleukin-6/metabolism , Lipopeptides/antagonists & inhibitors , Lipopeptides/pharmacology , Lipopolysaccharides , Male , Pandemics , Pneumonia/chemically induced , Pneumonia/metabolism , Pneumonia, Viral/genetics , Rats , SARS-CoV-2 , Signal Transduction/drug effects , Thrombin/metabolism , Toll-Like Receptors/metabolism
7.
Immunity ; 54(7): 1463-1477.e11, 2021 07 13.
Article in English | MEDLINE | ID: covidwho-1263294

ABSTRACT

Acute respiratory distress syndrome (ARDS), an inflammatory condition with high mortality rates, is common in severe COVID-19, whose risk is reduced by metformin rather than other anti-diabetic medications. Detecting of inflammasome assembly in post-mortem COVID-19 lungs, we asked whether and how metformin inhibits inflammasome activation while exerting its anti-inflammatory effect. We show that metformin inhibited NLRP3 inflammasome activation and interleukin (IL)-1ß production in cultured and alveolar macrophages along with inflammasome-independent IL-6 secretion, thus attenuating lipopolysaccharide (LPS)- and SARS-CoV-2-induced ARDS. By targeting electron transport chain complex 1 and independently of AMP-activated protein kinase (AMPK) or NF-κB, metformin blocked LPS-induced and ATP-dependent mitochondrial (mt) DNA synthesis and generation of oxidized mtDNA, an NLRP3 ligand. Myeloid-specific ablation of LPS-induced cytidine monophosphate kinase 2 (CMPK2), which is rate limiting for mtDNA synthesis, reduced ARDS severity without a direct effect on IL-6. Thus, inhibition of ATP and mtDNA synthesis is sufficient for ARDS amelioration.


Subject(s)
Adenosine Triphosphate/metabolism , DNA, Mitochondrial/biosynthesis , Inflammasomes/drug effects , Metformin/pharmacology , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Pneumonia/prevention & control , Animals , COVID-19/metabolism , COVID-19/prevention & control , Cytokines/genetics , Cytokines/metabolism , DNA, Mitochondrial/metabolism , Humans , Inflammasomes/metabolism , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Lipopolysaccharides/toxicity , Metformin/therapeutic use , Mice , Nucleoside-Phosphate Kinase/metabolism , Pneumonia/metabolism , Respiratory Distress Syndrome/chemically induced , Respiratory Distress Syndrome/prevention & control , SARS-CoV-2/pathogenicity
8.
Mol Ther ; 29(8): 2424-2440, 2021 08 04.
Article in English | MEDLINE | ID: covidwho-1225433

ABSTRACT

Lung inflammation is a hallmark of coronavirus disease 2019 (COVID-19). In this study, we show that mice develop inflamed lung tissue after being administered exosomes released from the lung epithelial cells exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Nsp12 and Nsp13 (exosomesNsp12Nsp13). Mechanistically, we show that exosomesNsp12Nsp13 are taken up by lung macrophages, leading to activation of nuclear factor κB (NF-κB) and the subsequent induction of an array of inflammatory cytokines. Induction of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1ß from exosomesNsp12Nsp13-activated lung macrophages contributes to inducing apoptosis in lung epithelial cells. Induction of exosomesNsp12Nsp13-mediated lung inflammation was abolished with ginger exosome-like nanoparticle (GELN) microRNA (miRNA aly-miR396a-5p. The role of GELNs in inhibition of the SARS-CoV-2-induced cytopathic effect (CPE) was further demonstrated via GELN aly-miR396a-5p- and rlcv-miR-rL1-28-3p-mediated inhibition of expression of Nsp12 and spike genes, respectively. Taken together, our results reveal exosomesNsp12Nsp13 as potentially important contributors to the development of lung inflammation, and GELNs are a potential therapeutic agent to treat COVID-19.


Subject(s)
COVID-19/metabolism , Exosomes/metabolism , MicroRNAs/metabolism , Plants/metabolism , Pneumonia/metabolism , A549 Cells , Animals , Cell Line , Cell Line, Tumor , Chlorocebus aethiops , Cytokines/metabolism , Epithelial Cells/metabolism , Humans , Interleukin-6/metabolism , Macrophages, Alveolar/metabolism , Male , Mice , Mice, Inbred C57BL , NF-kappa B/metabolism , SARS-CoV-2/pathogenicity , Tumor Necrosis Factor-alpha/metabolism , U937 Cells , Vero Cells
9.
Respir Res ; 22(1): 99, 2021 Apr 06.
Article in English | MEDLINE | ID: covidwho-1169963

ABSTRACT

BACKGROUND: COVID-19 pneumonia has been associated with severe acute hypoxia, sepsis-like states, thrombosis and chronic sequelae including persisting hypoxia and fibrosis. The molecular hypoxia response pathway has been associated with such pathologies and our recent observations on anti-hypoxic and anti-inflammatory effects of whole aqueous extract of Adhatoda Vasica (AV) prompted us to explore its effects on relevant preclinical mouse models. METHODS: In this study, we tested the effect of whole aqueous extract of AV, in murine models of bleomycin induced pulmonary fibrosis, Cecum Ligation and Puncture (CLP) induced sepsis, and siRNA induced hypoxia-thrombosis phenotype. The effect on lung of AV treated naïve mice was also studied at transcriptome level. We also determined if the extract may have any effect on SARS-CoV2 replication. RESULTS: Oral administration AV extract attenuates increased airway inflammation, levels of transforming growth factor-ß1 (TGF-ß1), IL-6, HIF-1α and improves the overall survival rates of mice in the models of pulmonary fibrosis and sepsis and rescues the siRNA induced inflammation and associated blood coagulation phenotypes in mice. We observed downregulation of hypoxia, inflammation, TGF-ß1, and angiogenesis genes and upregulation of adaptive immunity-related genes in the lung transcriptome. AV treatment also reduced the viral load in Vero cells infected with SARS-CoV2. CONCLUSION: Our results provide a scientific rationale for this ayurvedic herbal medicine in ameliorating the hypoxia-hyperinflammation features and highlights the repurposing potential of AV in COVID-19-like conditions.


Subject(s)
Anti-Inflammatory Agents/pharmacology , COVID-19/drug therapy , Drug Repositioning , Hypoxia/drug therapy , Justicia , Lung/drug effects , Plant Extracts/pharmacology , Pneumonia/prevention & control , Pulmonary Fibrosis/drug therapy , Sepsis/drug therapy , Animals , Anti-Inflammatory Agents/isolation & purification , Bleomycin , COVID-19/metabolism , COVID-19/virology , Cecum/microbiology , Cecum/surgery , Cytokines/genetics , Cytokines/metabolism , Disease Models, Animal , Hypoxia/genetics , Hypoxia/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Hypoxia-Inducible Factor-Proline Dioxygenases/genetics , Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism , Inflammation Mediators/metabolism , Justicia/chemistry , Ligation , Lung/metabolism , Lung/microbiology , Lung/pathology , Male , Mice, Inbred BALB C , Mice, Inbred C57BL , Plant Extracts/isolation & purification , Pneumonia/genetics , Pneumonia/metabolism , Pneumonia/microbiology , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/genetics , Pulmonary Fibrosis/metabolism , RNA Interference , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Sepsis/genetics , Sepsis/metabolism , Sepsis/microbiology , Transcriptome
11.
Nat Commun ; 12(1): 1386, 2021 03 02.
Article in English | MEDLINE | ID: covidwho-1114712

ABSTRACT

The COVID-19 pandemic is a global health crisis that poses a great challenge to the public health system of affected countries. Safe and effective vaccines are needed to overcome this crisis. Here, we develop and assess the protective efficacy and immunogenicity of an inactivated SARS-CoV-2 vaccine in rhesus macaques. Twenty macaques were divided into four groups of five animals each. One group was administered a placebo, while three groups were immunized with three different vaccine candidates of BBV152 at 0 and 14 days. All the macaques were challenged with SARS-CoV-2 fourteen days after the second dose. The protective response was observed with increasing SARS-CoV-2 specific IgG and neutralizing antibody titers from 3rd-week post-immunization. Viral clearance was observed from bronchoalveolar lavage fluid, nasal swab, throat swab and lung tissues at 7 days post-infection in the vaccinated groups. No evidence of pneumonia was observed by histopathological examination in vaccinated groups, unlike the placebo group which exhibited interstitial pneumonia and localization of viral antigen in the alveolar epithelium and macrophages by immunohistochemistry. This vaccine candidate BBV152 has completed Phase I/II (NCT04471519) clinical trials in India and is presently in phase III, data of this study substantiates the immunogenicity and protective efficacy of the vaccine candidates.


Subject(s)
COVID-19 Vaccines/therapeutic use , SARS-CoV-2/pathogenicity , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Enzyme-Linked Immunosorbent Assay , Female , Immunohistochemistry , Lymphocytes/immunology , Lymphocytes/metabolism , Macaca mulatta , Male , Pneumonia/immunology , Pneumonia/metabolism
12.
Molecules ; 26(1)2020 Dec 31.
Article in English | MEDLINE | ID: covidwho-1006941

ABSTRACT

December 2019 saw the emergence of the coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which has spread across the globe. The high infectivity and ongoing mortality of SARS-CoV-2 emphasize the demand of drug discovery. Angiotensin-converting enzyme II (ACE2) is the functional receptor for SARS-CoV-2 entry into host cells. ACE2 exists as a membrane-bound protein on major viral target pulmonary epithelial cells, and its peptidase domain (PD) interacts SARS-CoV-2 spike protein with higher affinity. Therefore, targeting ACE2 is an important pharmacological intervention for a SARS-CoV-2 infection. In this review, we described the two-way switch role of ACE2 in the treatment of novel coronavirus pneumonia and underlying comorbidities, and discussed the potential effect of the ACE inhibitor and angiotensin receptor blocker on a hypertension patient with the SARS-CoV-2 infection. In addition, we analyzed the S-protein-binding site on ACE2 and suggested that blocking hot spot-31 and hot spot-353 on ACE2 could be a therapeutic strategy for preventing the spread of SARS-CoV-2. Besides, the recombinant ACE2 protein could be another potential treatment option for SARS-CoV-2 induced acute severe lung failure. This review could provide beneficial information for the development of anti-SARS-CoV-2 agents via targeting ACE2 and the clinical usage of renin-angiotensin system (RAS) drugs for novel coronavirus pneumonia treatment.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Pneumonia/drug therapy , Pneumonia/metabolism , SARS-CoV-2/drug effects , Animals , COVID-19/metabolism , COVID-19/virology , Humans , Pneumonia/virology
13.
PLoS One ; 15(11): e0241663, 2020.
Article in English | MEDLINE | ID: covidwho-910303

ABSTRACT

BACKGROUND/AIM: The coronavirus disease 2019 (COVID-19) had become a big threat worldwide. Liver injury is not uncommon in patients with COVID-19, and clarifying its characteristics is needed. This study aimed to identify factors associated with liver injury and to develop a new classification of predictive severity in patients with COVID-19. METHODS: Confirmed patients with COVID-19 (n = 60) were recruited retrospectively from Musashino Red Cross Hospital. The factors of liver injury especially on the elevation of liver enzymes (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) were analyzed. Grading was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. RESULTS: During a median hospitalization follow-up of 15 (4-41) days, 51 (85.0%) patients had COVID-19 pneumonia. In clinical courses, oxygenation was needed for 25 (41.6%) patients and intubation was needed for 9 (15.0%) patients. A total of 27 (45.0%) patients had gastrointestinal symptoms (GS), such as appetite loss, diarrhea, and nausea. A logistic regression analysis revealed that C-reactive protein (CRP) at baseline, oxygenation, intubation, and GS were significant factors of liver injury. Based on these results, patients were classified into three groups: group 1, no oxygenation pneumonia; group 2, pneumonia with oxygenation or GS; and group 3, intubation. We classified 25 (41.7%), 26 (43.3%), and 9 (15.0%) patients into mild, moderate, and severe groups, respectively. The peak of AST and ALT levels was significantly stratified with this criteria (mild [median AST, 28 IU/L; median ALT, 33 IU/L], moderate [median AST, 48 IU/L; median ALT, 47.5 IU/L], and severe [median AST, 109 IU/L; median ALT, 106 IU/L]; P<0.001 and P = 0.0114, respectively). CONCLUSION: COVID-19-related liver injury was significantly stratified based on GS and severity of pneumonia.


Subject(s)
Coronavirus Infections/pathology , Digestive System Diseases/pathology , Digestive System Diseases/virology , Liver Diseases/pathology , Liver Diseases/virology , Pneumonia, Viral/pathology , Pneumonia/pathology , Pneumonia/virology , Alanine Transaminase/metabolism , Aspartate Aminotransferases/metabolism , C-Reactive Protein/metabolism , COVID-19 , Digestive System Diseases/metabolism , Female , Follow-Up Studies , Humans , Liver/metabolism , Liver/pathology , Liver/virology , Liver Diseases/metabolism , Male , Middle Aged , Pandemics , Pneumonia/metabolism , Retrospective Studies , Severity of Illness Index
14.
BMJ Open Respir Res ; 7(1)2020 09.
Article in English | MEDLINE | ID: covidwho-760259

ABSTRACT

We and others propose vimentin as a possible cellular target for the treatment of COVID-19. This innovative idea is so recent that it requires further attention and debate. The significant role played by vimentin in virus-induced infection however is well established: (1) vimentin has been reported as a co-receptor and/or attachment site for SARS-CoV; (2) vimentin is involved in viral replication in cells; (3) vimentin plays a fundamental role in both the viral infection and the consequent explosive immune-inflammatory response and (4) a lower vimentin expression is associated with the inhibition of epithelial to mesenchymal transition and fibrosis. Moreover, the absence of vimentin in mice makes them resistant to lung injury. Since vimentin has a twofold role in the disease, not only being involved in the viral infection but also in the associated life-threatening lung inflammation, the use of vimentin-targeted drugs may offer a synergistic advantage as compared with other treatments not targeting vimentin. Consequently, we speculate here that drugs which decrease the expression of vimentin can be used for the treatment of patients with COVID-19 and advise that several Food and Drug Administration-approved drugs be immediately tested in clinical trials against SARS-CoV-2, thus broadening therapeutic options for this type of viral infection.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/physiology , Coronavirus Infections , Pandemics , Pneumonia, Viral , Vimentin/physiology , Virus Internalization/drug effects , Animals , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Down-Regulation , Drug Discovery/methods , Humans , Mice , Pneumonia/drug therapy , Pneumonia/immunology , Pneumonia/metabolism , Pneumonia, Viral/drug therapy , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , Receptors, Virus , SARS-CoV-2 , Virus Replication/physiology
15.
J Cell Mol Med ; 24(16): 9478-9482, 2020 08.
Article in English | MEDLINE | ID: covidwho-635772

ABSTRACT

Recent retrospective studies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) revealed that the patients with common comorbidities of cancers and chronic diseases face significantly poorer clinical outcomes than those without. Since the expression profile of ACE2, a crucial cell entry receptor for SARS-CoV-2, could indicate the susceptibility to SARS-CoV-2 infection, here we systematically dissected ACE2 expression using large-scale multi-omics data from 30 organs/tissues, 33 cancer types and some common chronic diseases involving >28 000 samples. It was found that sex and age could be correlated with the susceptibility of SARS-CoV-2 infection for certain tissues. Strikingly, ACE2 was up-regulated in cervical squamous cell carcinoma and endocervical adenocarcinoma, colon adenocarcinoma, oesophageal carcinoma, kidney renal papillary cell carcinoma, lung adenocarcinoma and uterine corpus endometrial carcinoma compared to controls. Furthermore, the patients with common chronic diseases regarding angiocardiopathy, type 2 diabetes, liver, pneumonia and hypertension were also with higher ACE2 expression compared to related controls, which were validated using independent data sets. Collectively, our study may reveal a novel important mechanism that the patients with certain cancers and chronic diseases may express higher ACE2 expression compared to the individuals without diseases, which could lead to their higher susceptibility to multi-organ injury of SARS-CoV-2 infection.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Neoplasms/metabolism , Receptors, Virus/metabolism , Adult , Age Factors , Aged , Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , COVID-19/metabolism , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/metabolism , Female , Gene Expression Regulation/genetics , Gene Expression Regulation, Neoplastic/genetics , Gene Regulatory Networks , Humans , Hypertension/genetics , Hypertension/metabolism , Male , Middle Aged , Neoplasms/genetics , Pneumonia/genetics , Pneumonia/metabolism , Retrospective Studies , Risk Factors , Sex Factors , Up-Regulation
16.
Am J Respir Crit Care Med ; 202(6): 812-821, 2020 09 15.
Article in English | MEDLINE | ID: covidwho-614625

ABSTRACT

Rationale: Coronavirus disease (COVID-19) is a global threat to health. Its inflammatory characteristics are incompletely understood.Objectives: To define the cytokine profile of COVID-19 and to identify evidence of immunometabolic alterations in those with severe illness.Methods: Levels of IL-1ß, IL-6, IL-8, IL-10, and sTNFR1 (soluble tumor necrosis factor receptor 1) were assessed in plasma from healthy volunteers, hospitalized but stable patients with COVID-19 (COVIDstable patients), patients with COVID-19 requiring ICU admission (COVIDICU patients), and patients with severe community-acquired pneumonia requiring ICU support (CAPICU patients). Immunometabolic markers were measured in circulating neutrophils from patients with severe COVID-19. The acute phase response of AAT (alpha-1 antitrypsin) to COVID-19 was also evaluated.Measurements and Main Results: IL-1ß, IL-6, IL-8, and sTNFR1 were all increased in patients with COVID-19. COVIDICU patients could be clearly differentiated from COVIDstable patients, and demonstrated higher levels of IL-1ß, IL-6, and sTNFR1 but lower IL-10 than CAPICU patients. COVID-19 neutrophils displayed altered immunometabolism, with increased cytosolic PKM2 (pyruvate kinase M2), phosphorylated PKM2, HIF-1α (hypoxia-inducible factor-1α), and lactate. The production and sialylation of AAT increased in COVID-19, but this antiinflammatory response was overwhelmed in severe illness, with the IL-6:AAT ratio markedly higher in patients requiring ICU admission (P < 0.0001). In critically unwell patients with COVID-19, increases in IL-6:AAT predicted prolonged ICU stay and mortality, whereas improvement in IL-6:AAT was associated with clinical resolution (P < 0.0001).Conclusions: The COVID-19 cytokinemia is distinct from that of other types of pneumonia, leading to organ failure and ICU need. Neutrophils undergo immunometabolic reprogramming in severe COVID-19 illness. Cytokine ratios may predict outcomes in this population.


Subject(s)
Acute-Phase Reaction/immunology , Carrier Proteins/metabolism , Coronavirus Infections/immunology , Coronavirus Infections/metabolism , Cytokines/immunology , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Lactic Acid/metabolism , Membrane Proteins/metabolism , Pneumonia, Viral/immunology , Pneumonia, Viral/metabolism , Thyroid Hormones/metabolism , alpha 1-Antitrypsin/immunology , Acute-Phase Reaction/metabolism , Adult , Aged , Betacoronavirus , Blotting, Western , COVID-19 , Case-Control Studies , Community-Acquired Infections/immunology , Community-Acquired Infections/metabolism , Coronavirus Infections/mortality , Coronavirus Infections/physiopathology , Critical Illness , Electrophoresis, Polyacrylamide Gel , Enzyme-Linked Immunosorbent Assay , Female , Hospitalization , Humans , Intensive Care Units , Interleukin-10/immunology , Interleukin-1beta/immunology , Interleukin-6/immunology , Interleukin-8/immunology , Length of Stay , Male , Middle Aged , Neutrophils/immunology , Neutrophils/metabolism , Pandemics , Phosphorylation , Pneumonia/immunology , Pneumonia/metabolism , Pneumonia, Viral/mortality , Pneumonia, Viral/physiopathology , Receptors, Tumor Necrosis Factor, Type I/immunology , SARS-CoV-2 , Severity of Illness Index , alpha 1-Antitrypsin/metabolism
18.
Int J Mol Med ; 46(1): 17-26, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-164754

ABSTRACT

In view of the emerging COVID­19 pandemic caused by SARS­CoV­2 virus, the search for potential protective and therapeutic antiviral strategies is of particular and urgent interest. Zinc is known to modulate antiviral and antibacterial immunity and regulate inflammatory response. Despite the lack of clinical data, certain indications suggest that modulation of zinc status may be beneficial in COVID­19. In vitro experiments demonstrate that Zn2+ possesses antiviral activity through inhibition of SARS­CoV RNA polymerase. This effect may underlie therapeutic efficiency of chloroquine known to act as zinc ionophore. Indirect evidence also indicates that Zn2+ may decrease the activity of angiotensin­converting enzyme 2 (ACE2), known to be the receptor for SARS­CoV­2. Improved antiviral immunity by zinc may also occur through up­regulation of interferon α production and increasing its antiviral activity. Zinc possesses anti­inflammatory activity by inhibiting NF­κB signaling and modulation of regulatory T­cell functions that may limit the cytokine storm in COVID­19. Improved Zn status may also reduce the risk of bacterial co­infection by improving mucociliary clearance and barrier function of the respiratory epithelium, as well as direct antibacterial effects against S. pneumoniae. Zinc status is also tightly associated with risk factors for severe COVID­19 including ageing, immune deficiency, obesity, diabetes, and atherosclerosis, since these are known risk groups for zinc deficiency. Therefore, Zn may possess protective effect as preventive and adjuvant therapy of COVID­19 through reducing inflammation, improvement of mucociliary clearance, prevention of ventilator­induced lung injury, modulation of antiviral and antibacterial immunity. However, further clinical and experimental studies are required.


Subject(s)
COVID-19/metabolism , COVID-19/prevention & control , Respiratory Tract Infections/metabolism , Respiratory Tract Infections/prevention & control , Zinc/therapeutic use , Angiotensin-Converting Enzyme 2/metabolism , Humans , Pandemics , Pneumonia/metabolism , Pneumonia/prevention & control , Risk Factors , SARS-CoV-2/pathogenicity
19.
Eur Respir J ; 56(1)2020 07.
Article in English | MEDLINE | ID: covidwho-143888

ABSTRACT

IMPORTANCE: Coronavirus disease 2019 (COVID-19), the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been declared a global pandemic with significant morbidity and mortality since first appearing in Wuhan, China, in late 2019. As many countries are grappling with the onset of their epidemics, pharmacotherapeutics remain lacking. The window of opportunity to mitigate downstream morbidity and mortality is narrow but remains open. The renin-angiotensin-aldosterone system (RAAS) is crucial to the homeostasis of both the cardiovascular and respiratory systems. Importantly, SARS-CoV-2 utilises and interrupts this pathway directly, which could be described as the renin-angiotensin-aldosterone-SARS-CoV (RAAS-SCoV) axis. There exists significant controversy and confusion surrounding how anti-hypertensive agents might function along this pathway. This review explores the current state of knowledge regarding the RAAS-SCoV axis (informed by prior studies of SARS-CoV), how this relates to our currently evolving pandemic, and how these insights might guide our next steps in an evidence-based manner. OBSERVATIONS: This review discusses the role of the RAAS-SCoV axis in acute lung injury and the effects, risks and benefits of pharmacological modification of this axis. There may be an opportunity to leverage the different aspects of RAAS inhibitors to mitigate indirect viral-induced lung injury. Concerns have been raised that such modulation might exacerbate the disease. While relevant preclinical, experimental models to date favour a protective effect of RAAS-SCoV axis inhibition on both lung injury and survival, clinical data related to the role of RAAS modulation in the setting of SARS-CoV-2 remain limited. CONCLUSION: Proposed interventions for SARS-CoV-2 predominantly focus on viral microbiology and aim to inhibit viral cellular injury. While these therapies are promising, immediate use may not be feasible, and the time window of their efficacy remains a major unanswered question. An alternative approach is the modulation of the specific downstream pathophysiological effects caused by the virus that lead to morbidity and mortality. We propose a preponderance of evidence that supports clinical equipoise regarding the efficacy of RAAS-based interventions, and the imminent need for a multisite randomised controlled clinical trial to evaluate the inhibition of the RAAS-SCoV axis on acute lung injury in COVID-19.


Subject(s)
Acute Lung Injury/metabolism , Angiotensin II/metabolism , Betacoronavirus/metabolism , Coronavirus Infections/metabolism , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/metabolism , Renin-Angiotensin System/physiology , Acute Lung Injury/physiopathology , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme 2 , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Animals , COVID-19 , Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/metabolism , Cardiovascular Diseases/physiopathology , Coronavirus Infections/drug therapy , Coronavirus Infections/physiopathology , Humans , Pandemics , Pneumonia/metabolism , Pneumonia/physiopathology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/physiopathology , Receptor, Angiotensin, Type 1/metabolism , Receptor, Angiotensin, Type 2 , SARS-CoV-2
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