Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 29
Filter
1.
Front Immunol ; 13: 834862, 2022.
Article in English | MEDLINE | ID: covidwho-1775666

ABSTRACT

Respiratory viral infections with SARS-CoV-2 and influenza viruses commonly induce a strong infiltration of immune cells into the human lung, with potential detrimental effects on the integrity of the lung tissue. Despite comprising the largest fractions of circulating lymphocytes in the lung, rather little is known about how peripheral blood natural killer (NK) cell and T cell subsets are equipped for lung-homing in COVID-19 and influenza. Here, we provide a detailed comparative analysis of NK cells and T cells in patients infected with SARS-CoV-2 or influenza virus, focusing on the protein and gene expression of chemokine receptors known to be involved in recruitment to the lung. For this, we used 28-colour flow cytometry as well as re-analysis of a publicly available single-cell RNA-seq dataset from bronchoalveolar lavage (BAL) fluid. Frequencies of NK cells and T cells expressing CXCR3, CXCR6, and CCR5 were altered in peripheral blood of COVID-19 and influenza patients, in line with increased transcript expression of CXCR3, CXCR6, and CCR5 and their respective ligands in BAL fluid. NK cells and T cells expressing lung-homing receptors displayed stronger phenotypic signs of activation compared to cells lacking lung-homing receptors, and activation was overall stronger in influenza compared to COVID-19. Together, our results indicate a role for CXCR3+, CXCR6+, and/or CCR5+ NK cells and T cells that potentially migrate to the lungs in moderate COVID-19 and influenza patients, identifying common targets for future therapeutic interventions in respiratory viral infections.


Subject(s)
COVID-19 , Influenza, Human , Gene Expression , Humans , Influenza, Human/metabolism , Killer Cells, Natural , Lung , SARS-CoV-2 , T-Lymphocyte Subsets
2.
Biochemistry (Mosc) ; 86(7): 800-817, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1594970

ABSTRACT

COVID-19, a new human respiratory disease that has killed nearly 3 million people in a year since the start of the pandemic, is a global public health challenge. Its infectious agent, SARS-CoV-2, differs from other coronaviruses in a number of structural features that make this virus more pathogenic and transmissible. In this review, we discuss some important characteristics of the main SARS-CoV-2 surface antigen, the spike (S) protein, such as (i) ability of the receptor-binding domain (RBD) to switch between the "standing-up" position (open pre-fusion conformation) for receptor binding and the "lying-down" position (closed pre-fusion conformation) for immune system evasion; (ii) advantage of a high binding affinity of the RBD open conformation to the human angiotensin-converting enzyme 2 (ACE2) receptor for efficient cell entry; and (iii) S protein preliminary activation by the intracellular furin-like proteases for facilitation of the virus spreading across different cell types. We describe interactions between the S protein and cellular receptors, co-receptors, and antagonists, as well as a hypothetical mechanism of the homotrimeric spike structure destabilization that triggers the fusion of the viral envelope with the cell membrane at physiological pH and mediates the viral nucleocapsid entry into the cytoplasm. The transition of the S protein pre-fusion conformation to the post-fusion one on the surface of virions after their treatment with some reagents, such as ß-propiolactone, is essential, especially in relation to the vaccine production. We also compare the COVID-19 pathogenesis with that of severe outbreaks of "avian" influenza caused by the A/H5 and A/H7 highly pathogenic viruses and discuss the structural similarities between the SARS-CoV-2 S protein and hemagglutinins of those highly pathogenic strains. Finally, we touch on the prospective and currently used COVID-19 antiviral and anti-pathogenetic therapeutics, as well as recently approved conventional and innovative COVID-19 vaccines and their molecular and immunological features.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Pandemics , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/epidemiology , COVID-19/genetics , COVID-19/metabolism , Humans , Influenza A virus/chemistry , Influenza A virus/genetics , Influenza A virus/metabolism , Influenza, Human/epidemiology , Influenza, Human/genetics , Influenza, Human/metabolism , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
3.
Int J Mol Sci ; 23(1)2021 Dec 24.
Article in English | MEDLINE | ID: covidwho-1580700

ABSTRACT

Acute respiratory distress syndrome (ARDS) followed by repair with lung remodeling is observed in COVID-19. These findings can lead to pulmonary terminal fibrosis, a form of irreversible sequelae. There is evidence that TGF-ß is intimately involved in the fibrogenic process. When activated, TGF-ß promotes the differentiation of fibroblasts into myofibroblasts and regulates the remodeling of the extracellular matrix (ECM). In this sense, the present study evaluated the histopathological features and immunohistochemical biomarkers (ACE-2, AKT-1, Caveolin-1, CD44v6, IL-4, MMP-9, α-SMA, Sphingosine-1, and TGF-ß1 tissue expression) involved in the TGF-ß1 signaling pathways and pulmonary fibrosis. The study consisted of 24 paraffin lung samples from patients who died of COVID-19 (COVID-19 group), compared to 10 lung samples from patients who died of H1N1pdm09 (H1N1 group) and 11 lung samples from patients who died of different causes, with no lung injury (CONTROL group). In addition to the presence of alveolar septal fibrosis, diffuse alveolar damage (DAD) was found to be significantly increased in the COVID-19 group, associated with a higher density of Collagen I (mature) and III (immature). There was also a significant increase observed in the immunoexpression of tissue biomarkers ACE-2, AKT-1, CD44v6, IL-4, MMP-9, α-SMA, Sphingosine-1, and TGF-ß1 in the COVID-19 group. A significantly lower expression of Caveolin-1 was also found in this group. The results suggest the participation of TGF-ß pathways in the development process of pulmonary fibrosis. Thus, it would be plausible to consider therapy with TGF-ß inhibitors in those patients recovered from COVID-19 to mitigate a possible development of pulmonary fibrosis and its consequences for post-COVID-19 life quality.


Subject(s)
COVID-19/metabolism , Pulmonary Fibrosis/metabolism , Signal Transduction , Transforming Growth Factor beta/metabolism , Actins/metabolism , Adrenal Cortex Hormones/therapeutic use , Adult , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/complications , COVID-19/drug therapy , COVID-19/pathology , Caveolin 1/metabolism , Collagen Type I/metabolism , Collagen Type III/metabolism , Female , Humans , Hyaluronan Receptors/metabolism , Immunohistochemistry , Influenza A Virus, H1N1 Subtype/metabolism , Influenza, Human/metabolism , Influenza, Human/pathology , Interleukin-4/metabolism , Male , Matrix Metalloproteinase 9/metabolism , Middle Aged , Proto-Oncogene Proteins c-akt/metabolism , Pulmonary Fibrosis/complications , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/pathology , Retrospective Studies , Transforming Growth Factor beta1/metabolism
4.
Crit Care ; 25(1): 390, 2021 11 15.
Article in English | MEDLINE | ID: covidwho-1518286

ABSTRACT

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a type of respiratory failure characterized by lung inflammation and pulmonary edema. Coronavirus disease 2019 (COVID-19) is associated with ARDS in the more severe cases. This study aimed to compare the specificity of the metabolic alterations induced by COVID-19 or Influenza A pneumonia (IAP) in ARDS. METHODS: Eighteen patients with ARDS due to COVID-19 and twenty patients with ARDS due to IAP, admitted to the intensive care unit. ARDS was defined as in the American-European Consensus Conference. As compared with patients with COVID-19, patients with IAP were younger and received more often noradrenaline to maintain a mean arterial pressure > 65 mm Hg. Serum samples were analyzed by Nuclear Magnetic Resonance Spectroscopy. Multivariate Statistical Analyses were used to identify metabolic differences between groups. Metabolic pathway analysis was performed to identify the most relevant pathways involved in ARDS development. RESULTS: ARDS due to COVID-19 or to IAP induces a different regulation of amino acids metabolism, lipid metabolism, glycolysis, and anaplerotic metabolism. COVID-19 causes a significant energy supply deficit that induces supplementary energy-generating pathways. In contrast, IAP patients suffer more marked inflammatory and oxidative stress responses. The classificatory model discriminated against the cause of pneumonia with a success rate of 100%. CONCLUSIONS: Our findings support the concept that ARDS is associated with a characteristic metabolomic profile that may discriminate patients with ARDS of different etiologies, being a potential biomarker for the diagnosis, prognosis, and management of this condition.


Subject(s)
COVID-19/metabolism , Influenza A Virus, H1N1 Subtype , Influenza, Human/metabolism , Respiratory Distress Syndrome/metabolism , Adult , Aged , COVID-19/complications , Female , Humans , Influenza, Human/complications , Male , Middle Aged , Respiratory Distress Syndrome/virology
5.
mBio ; 11(2)2020 03 03.
Article in English | MEDLINE | ID: covidwho-1452919

ABSTRACT

Obesity is associated with increased disease severity, elevated viral titers in exhaled breath, and significantly prolonged viral shed during influenza A virus infection. Due to the mutable nature of RNA viruses, we questioned whether obesity could also influence influenza virus population diversity. Here, we show that minor variants rapidly emerge in obese mice. The variants exhibit increased viral replication, resulting in enhanced virulence in wild-type mice. The increased diversity of the viral population correlated with decreased type I interferon responses, and treatment of obese mice with recombinant interferon reduced viral diversity, suggesting that the delayed antiviral response exhibited in obesity permits the emergence of a more virulent influenza virus population. This is not unique to obese mice. Obesity-derived normal human bronchial epithelial (NHBE) cells also showed decreased interferon responses and increased viral replication, suggesting that viral diversity also was impacted in this increasing population.IMPORTANCE Currently, 50% of the adult population worldwide is overweight or obese. In these studies, we demonstrate that obesity not only enhances the severity of influenza infection but also impacts viral diversity. The altered microenvironment associated with obesity supports a more diverse viral quasispecies and affords the emergence of potentially pathogenic variants capable of inducing greater disease severity in lean hosts. This is likely due to the impaired interferon response, which is seen in both obese mice and obesity-derived human bronchial epithelial cells, suggesting that obesity, aside from its impact on influenza virus pathogenesis, permits the stochastic accumulation of potentially pathogenic viral variants, raising concerns about its public health impact as the prevalence of obesity continues to rise.


Subject(s)
Disease Susceptibility , Influenza A virus/physiology , Influenza, Human/etiology , Obesity/complications , Animals , Host-Pathogen Interactions , Humans , Influenza, Human/metabolism , Mice , Mutation , Phenotype , RNA, Viral , Respiratory Mucosa/metabolism , Respiratory Mucosa/virology , Severity of Illness Index , Virulence , Virus Replication
6.
EBioMedicine ; 71: 103546, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1363149

ABSTRACT

BACKGROUND: Respiratory virus infections are significant causes of morbidity and mortality, and may induce host metabolite alterations by infecting respiratory epithelial cells. We investigated the use of liquid chromatography quadrupole time-of-flight mass spectrometry (LC/Q-TOF) combined with machine learning for the diagnosis of influenza infection. METHODS: We analyzed nasopharyngeal swab samples by LC/Q-TOF to identify distinct metabolic signatures for diagnosis of acute illness. Machine learning models were performed for classification, followed by Shapley additive explanation (SHAP) analysis to analyze feature importance and for biomarker discovery. FINDINGS: A total of 236 samples were tested in the discovery phase by LC/Q-TOF, including 118 positive samples (40 influenza A 2009 H1N1, 39 influenza H3 and 39 influenza B) as well as 118 age and sex-matched negative controls with acute respiratory illness. Analysis showed an area under the receiver operating characteristic curve (AUC) of 1.00 (95% confidence interval [95% CI] 0.99, 1.00), sensitivity of 1.00 (95% CI 0.86, 1.00) and specificity of 0.96 (95% CI 0.81, 0.99). The metabolite most strongly associated with differential classification was pyroglutamic acid. Independent validation of a biomarker signature based on the top 20 differentiating ion features was performed in a prospective cohort of 96 symptomatic individuals including 48 positive samples (24 influenza A 2009 H1N1, 5 influenza H3 and 19 influenza B) and 48 negative samples. Testing performed using a clinically-applicable targeted approach, liquid chromatography triple quadrupole mass spectrometry, showed an AUC of 1.00 (95% CI 0.998, 1.00), sensitivity of 0.94 (95% CI 0.83, 0.98), and specificity of 1.00 (95% CI 0.93, 1.00). Limitations include lack of sample suitability assessment, and need to validate these findings in additional patient populations. INTERPRETATION: This metabolomic approach has potential for diagnostic applications in infectious diseases testing, including other respiratory viruses, and may eventually be adapted for point-of-care testing. FUNDING: None.


Subject(s)
Influenza, Human/diagnosis , Machine Learning , Metabolome , Molecular Diagnostic Techniques/methods , Adolescent , Adult , Child , Child, Preschool , Female , Gas Chromatography-Mass Spectrometry/methods , Humans , Influenza, Human/metabolism , Influenza, Human/virology , Male , Metabolomics/methods , Nasal Mucosa/metabolism , Nasal Mucosa/virology , Orthomyxoviridae/pathogenicity , Pyrrolidonecarboxylic Acid/analysis
7.
Cell Rep ; 31(11): 107772, 2020 06 16.
Article in English | MEDLINE | ID: covidwho-1385222

ABSTRACT

ISG15 is a ubiquitin-like modifier that also functions extracellularly, signaling through the LFA-1 integrin to promote interferon (IFN)-γ release from natural killer (NK) and T cells. The signals that lead to the production of extracellular ISG15 and the relationship between its two core functions remain unclear. We show that both epithelial cells and lymphocytes can secrete ISG15, which then signals in either an autocrine or paracrine manner to LFA-1-expressing cells. Microbial pathogens and Toll-like receptor (TLR) agonists result in both IFN-ß-dependent and -independent secretion of ISG15, and residues required for ISG15 secretion are mapped. Intracellular ISGylation inhibits secretion, and viral effector proteins, influenza B NS1, and viral de-ISGylases, including SARS-CoV-2 PLpro, have opposing effects on secretion of ISG15. These results establish extracellular ISG15 as a cytokine-like protein that bridges early innate and IFN-γ-dependent immune responses, and indicate that pathogens have evolved to differentially inhibit the intracellular and extracellular functions of ISG15.


Subject(s)
Cytokines/metabolism , Signal Transduction , Ubiquitins/metabolism , Animals , HEK293 Cells , Humans , Influenza, Human/immunology , Influenza, Human/metabolism , Interferon-gamma/immunology , Interferon-gamma/metabolism , Jurkat Cells , Mice , Mice, Inbred C57BL , Mycobacterium Infections/immunology , Mycobacterium Infections/metabolism , Pathogen-Associated Molecular Pattern Molecules , Typhoid Fever/immunology , Typhoid Fever/metabolism , Viral Nonstructural Proteins/metabolism
8.
Mucosal Immunol ; 14(6): 1224-1234, 2021 11.
Article in English | MEDLINE | ID: covidwho-1387186

ABSTRACT

Epidemiological evidence establishes obesity as an independent risk factor for increased susceptibility and severity to viral respiratory pneumonias associated with H1N1 influenza and SARS-CoV-2 pandemics. Given the global obesity prevalence, a better understanding of the mechanisms behind obese susceptibility to infection is imperative. Altered immune cell metabolism and function are often perceived as a key causative factor of dysregulated inflammation. However, the contribution of adipocytes, the dominantly altered cell type in obesity with broad inflammatory properties, to infectious disease pathogenesis remains largely ignored. Thus, skewing of adipocyte-intrinsic cellular metabolism may lead to the development of pathogenic inflammatory adipocytes, which shape the overall immune responses by contributing to either premature immunosenescence, delayed hyperinflammation, or cytokine storm in infections. In this review, we discuss the underappreciated contribution of adipocyte cellular metabolism and adipocyte-produced mediators on immune system modulation and how such interplay may modify disease susceptibility and pathogenesis of influenza and SARS-CoV-2 infections in obese individuals.


Subject(s)
Adipocytes/metabolism , COVID-19/metabolism , Influenza A Virus, H1N1 Subtype/metabolism , Influenza, Human/metabolism , SARS-CoV-2/metabolism , Adipocytes/pathology , Adipocytes/virology , COVID-19/pathology , Humans , Inflammation/metabolism , Inflammation/pathology , Inflammation/virology , Influenza, Human/pathology
9.
Sci Rep ; 11(1): 12948, 2021 06 21.
Article in English | MEDLINE | ID: covidwho-1279894

ABSTRACT

COVID 19 disease has become a global catastrophe over the past year that has claimed the lives of over two million people around the world. Despite the introduction of vaccines against the disease, there is still a long way to completely eradicate it. There are concerns about the complications following infection with SARS-CoV-2. This research aimed to evaluate the possible correlation between infection with SARS-CoV viruses and cancer in an in-silico study model. To do this, the relevent dataset was selected from GEO database. Identification of differentially expressed genes among defined groups including SARS-CoV, SARS-dORF6, SARS-BatSRBD, and H1N1 were screened where the |Log FC| ≥ 1and p < 0.05 were considered statistically significant. Later, the pathway enrichment analysis and gene ontology (GO) were used by Enrichr and Shiny GO databases. Evaluation with STRING online was applied to predict the functional interactions of proteins, followed by Cytoscape analysis to identify the master genes. Finally, analysis with GEPIA2 server was carried out to reveal the possible correlation between candidate genes and cancer development. The results showed that the main molecular function of up- and down-regulated genes was "double-stranded RNA binding" and actin-binding, respectively. STRING and Cytoscape analysis presented four genes, PTEN, CREB1, CASP3, and SMAD3 as the key genes involved in cancer development. According to TCGA database results, these four genes were up-regulated notably in pancreatic adenocarcinoma. Our findings suggest that pancreatic adenocarcinoma is the most probably malignancy happening after infection with SARS-CoV family.


Subject(s)
Adenocarcinoma/etiology , COVID-19/complications , Carcinogenesis/genetics , Influenza A Virus, H1N1 Subtype , Influenza, Human/complications , Pancreatic Neoplasms/etiology , SARS Virus , SARS-CoV-2 , Severe Acute Respiratory Syndrome/complications , COVID-19/genetics , COVID-19/metabolism , COVID-19/virology , Caspase 3/genetics , Cyclic AMP Response Element-Binding Protein/genetics , Gene Expression Regulation , Gene Ontology , Humans , Influenza, Human/genetics , Influenza, Human/metabolism , Influenza, Human/virology , PTEN Phosphohydrolase/genetics , Protein Interaction Maps , Risk , Severe Acute Respiratory Syndrome/genetics , Severe Acute Respiratory Syndrome/metabolism , Severe Acute Respiratory Syndrome/virology , Signal Transduction/genetics , Smad3 Protein/genetics , Up-Regulation/genetics
10.
J Med Virol ; 93(4): 2396-2405, 2021 04.
Article in English | MEDLINE | ID: covidwho-1217389

ABSTRACT

SARS-CoV-2 triggers a dysregulated innate immune system activation. As the mevalonate pathway (MVP) prevents the activation of inflammasomes and cytokine release and regulates endosomal transport, compromised signaling could be associated with the pathobiology of COVID-19. Prior transcriptomic studies of host cells in response to SARS-CoV-2 infection have not reported to date the effects of SARS-CoV-2 on the MVP. In this study, we accessed public data sets to report in silico investigations into gene expression. In addition, we proposed candidate genes that are thought to have a direct association with the pathogenesis of COVID-19, and which may be dependent on signals derived from the MVP. Our results revealed dysregulation of genes involved in the MVP. These results were not found when investigating the gene expression data from host cells infected with H3N2 influenza virus, H1N1 influenza virus, or respiratory syncytial virus. Our manually curated gene set showed significant gene expression variability in A549 cells infected with SARS-CoV-2, as per Blanco-Melo et al. data set (GSE147507). In light of the present findings, SARS-CoV-2 could hijack the MVP, leading to hyperinflammatory responses. Prompt reconstitution of this pathway with available agents should be considered in future studies.


Subject(s)
COVID-19/metabolism , Mevalonic Acid/metabolism , SARS-CoV-2/metabolism , A549 Cells , Autophagy , COVID-19/genetics , COVID-19/immunology , COVID-19/virology , Computer Simulation , Cytokines/immunology , Cytokines/metabolism , HMGB1 Protein/genetics , HMGB1 Protein/metabolism , Host-Pathogen Interactions , Humans , Influenza A Virus, H1N1 Subtype/genetics , Influenza A Virus, H1N1 Subtype/metabolism , Influenza A Virus, H3N2 Subtype/genetics , Influenza A Virus, H3N2 Subtype/metabolism , Influenza, Human/immunology , Influenza, Human/metabolism , SAM Domain and HD Domain-Containing Protein 1/genetics , SAM Domain and HD Domain-Containing Protein 1/metabolism , SARS-CoV-2/genetics , Signal Transduction , Transcriptome , Virus Replication
11.
Biochem Biophys Res Commun ; 556: 87-92, 2021 06 04.
Article in English | MEDLINE | ID: covidwho-1173393

ABSTRACT

Virus-induced cytokine storm has been a devastating actuality in clinic. The abnormal production of type I interferon (IFN-1) and upregulation of multiple cytokines induced strong inflammation and thus lead to shock and organ failure. As an E3 ubiquitin ligase, tripartite motif-containing 37 (TRIM37) regulates the ubiquitination of multiple proteins including TRAFs. RNA sequencing was performed to investigated the alteration of transcriptional profile of H1N1-infected patients. qRT-PCR assay was performed to investigate the RNA levels of certain genes. The group of immune cells was examined by the Flow cytometry analysis. H&E staining was applied to evaluate lung inflammation of WT and TRIM37-KO mice. ELISA assay was performed to demonstrate the alteration of multiple cytokines. The protein levels in NF-kB signaling was estimated by western blotting and immunoprecipitation assays were applied to demonstrate the direct interaction between TRIM37 and TRAF-6. The RNA level of TRIM37 decreased in CD11b+ cells of Flu-infected patients. Knockout of TRIM37 inhibited the immune responses of H1N1-infected mice. TRIM37 deficiency reduced the levels of virous proinflammatory cytokines in bone marrow derived macrophages (BMDMs). Mechanically, TRIM37 promoted the K63-linked ubiquitination of TRAF6. TRIM37 negatively regulated inflammatory responses induced by virus infection via promoting TRAF6 ubiquitination at K63.


Subject(s)
Inflammation/metabolism , Orthomyxoviridae Infections/metabolism , Orthomyxoviridae Infections/virology , TNF Receptor-Associated Factor 6/metabolism , Tripartite Motif Proteins/metabolism , Ubiquitin-Protein Ligases/metabolism , Ubiquitination , Animals , Female , Humans , Inflammation Mediators/antagonists & inhibitors , Inflammation Mediators/immunology , Influenza A Virus, H1N1 Subtype/immunology , Influenza, Human/genetics , Influenza, Human/immunology , Influenza, Human/metabolism , Influenza, Human/virology , Mice , Mice, Inbred C57BL , Orthomyxoviridae Infections/genetics , Orthomyxoviridae Infections/immunology , TNF Receptor-Associated Factor 6/chemistry , Tripartite Motif Proteins/deficiency , Tripartite Motif Proteins/genetics , Ubiquitin-Protein Ligases/deficiency , Ubiquitin-Protein Ligases/genetics
12.
BMC Complement Med Ther ; 21(1): 112, 2021 Apr 07.
Article in English | MEDLINE | ID: covidwho-1172831

ABSTRACT

BACKGROUND: Elderberry has traditionally been used to prevent and treat respiratory problems. During the COVID-19 pandemic, there has been interest in elderberry supplements to treat or prevent illness, but also concern that elderberry might overstimulate the immune system and increase the risk of 'cytokine storm'. We aimed to determine benefits and harms of elderberry for the prevention and treatment of viral respiratory infections, and to assess the relationship between elderberry supplements and negative health impacts associated with overproduction of pro-inflammatory cytokines. METHODS: We conducted a systematic review and searched six databases, four research registers, and two preprint sites for studies. Two reviewers independently assessed studies for inclusion, extracted data from studies, assessed risk of bias using Cochrane tools, and evaluated certainty of estimates using GRADE. Outcomes included new illnesses and the severity and duration of illness. RESULTS: We screened 1187 records and included five randomized trials on elderberry for the treatment or prevention of viral respiratory illness. We did not find any studies linking elderberry to clinical inflammatory outcomes. However, we found three studies measuring production of cytokines ex vivo after ingestion of elderberry. Elderberry may not reduce the risk of developing the common cold; it may reduce the duration and severity of colds, but the evidence is uncertain. Elderberry may reduce the duration of influenza but the evidence is uncertain. Compared to oseltamivir, an elderberry-containing product may be associated with a lower risk of influenza complications and adverse events. We did not find evidence on elderberry and clinical outcomes related to inflammation. However, we found evidence that elderberry has some effect on inflammatory markers, although this effect may decline with ongoing supplementation. One small study compared elderberry to diclofenac (a nonsteroidal anti-inflammatory drug) and provided some evidence that elderberry is as effective or less effective than diclofenac in cytokine reduction over time. CONCLUSIONS: Elderberry may be a safe option for treating viral respiratory illness, and there is no evidence that it overstimulates the immune system. However, the evidence on both benefits and harms is uncertain and information from recent and ongoing studies is necessary to make firm conclusions.


Subject(s)
COVID-19/drug therapy , Common Cold/drug therapy , Cytokines/metabolism , Influenza, Human/drug therapy , Phytotherapy , Plant Extracts/therapeutic use , Sambucus , COVID-19/metabolism , Common Cold/metabolism , Humans , Inflammation/metabolism , Inflammation/prevention & control , Influenza, Human/metabolism , Pandemics , SARS-CoV-2
13.
Am J Respir Cell Mol Biol ; 64(6): 687-697, 2021 06.
Article in English | MEDLINE | ID: covidwho-1143104

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly become a global pandemic. In addition to the acute pulmonary symptoms of coronavirus disease (COVID-19) (the disease associated with SARS-CoV-2 infection), pulmonary and distal coagulopathies have caused morbidity and mortality in many patients. Currently, the molecular pathogenesis underlying COVID-19-associated coagulopathies are unknown. Identifying the molecular basis of how SARS-CoV-2 drives coagulation is essential to mitigating short- and long-term thrombotic risks of sick and recovered patients with COVID-19. We aimed to perform coagulation-focused transcriptome analysis of in vitro infected primary respiratory epithelial cells, patient-derived bronchial alveolar lavage cells, and circulating immune cells during SARS-CoV-2 infection. Our objective was to identify transcription-mediated signaling networks driving coagulopathies associated with COVID-19. We analyzed recently published experimentally and clinically derived bulk or single-cell RNA sequencing datasets of SARS-CoV-2 infection to identify changes in transcriptional regulation of blood coagulation. We also confirmed that the transcriptional expression of a key coagulation regulator was recapitulated at the protein level. We specifically focused our analysis on lung tissue-expressed genes regulating the extrinsic coagulation cascade and the plasminogen activation system. Analyzing transcriptomic data of in vitro infected normal human bronchial epithelial cells and patient-derived bronchial alveolar lavage samples revealed that SARS-CoV-2 infection induces the extrinsic blood coagulation cascade and suppresses the plasminogen activation system. We also performed in vitro SARS-CoV-2 infection experiments on primary human lung epithelial cells to confirm that transcriptional upregulation of tissue factor, the extrinsic coagulation cascade master regulator, manifested at the protein level. Furthermore, infection of normal human bronchial epithelial cells with influenza A virus did not drive key regulators of blood coagulation in a similar manner as SARS-CoV-2. In addition, peripheral blood mononuclear cells did not differentially express genes regulating the extrinsic coagulation cascade or plasminogen activation system during SARS-CoV-2 infection, suggesting that they are not directly inducing coagulopathy through these pathways. The hyperactivation of the extrinsic blood coagulation cascade and the suppression of the plasminogen activation system in SARS-CoV-2-infected epithelial cells may drive diverse coagulopathies in the lung and distal organ systems. Understanding how hosts drive such transcriptional changes with SARS-CoV-2 infection may enable the design of host-directed therapeutic strategies to treat COVID-19 and other coronaviruses inducing hypercoagulation.


Subject(s)
Alveolar Epithelial Cells/metabolism , Blood Coagulation Disorders/metabolism , COVID-19/metabolism , Gene Expression Regulation , SARS-CoV-2/metabolism , Signal Transduction , Transcription, Genetic , Alveolar Epithelial Cells/pathology , Alveolar Epithelial Cells/virology , Blood Coagulation Disorders/etiology , Blood Coagulation Disorders/pathology , COVID-19/complications , COVID-19/pathology , Cell Line , Female , Humans , Influenza A virus/metabolism , Influenza, Human/complications , Influenza, Human/metabolism , Influenza, Human/pathology , Male
14.
JCI Insight ; 6(6)2021 03 22.
Article in English | MEDLINE | ID: covidwho-1088356

ABSTRACT

Regulatory T (Treg) cells orchestrate resolution and repair of acute lung inflammation and injury after viral pneumonia. Compared with younger patients, older individuals experience impaired recovery and worse clinical outcomes after severe viral infections, including influenza and SARS coronavirus 2 (SARS-CoV-2). Whether age is a key determinant of Treg cell prorepair function after lung injury remains unknown. Here, we showed that aging results in a cell-autonomous impairment of reparative Treg cell function after experimental influenza pneumonia. Transcriptional and DNA methylation profiling of sorted Treg cells provided insight into the mechanisms underlying their age-related dysfunction, with Treg cells from aged mice demonstrating both loss of reparative programs and gain of maladaptive programs. Strategies to restore youthful Treg cell functional programs could be leveraged as therapies to improve outcomes among older individuals with severe viral pneumonia.


Subject(s)
Aging/physiology , Influenza A virus , Influenza, Human/pathology , Lung/pathology , Pneumonia, Viral/pathology , SARS-CoV-2 , T-Lymphocytes, Regulatory/pathology , Age Factors , Aging/metabolism , Animals , COVID-19/complications , COVID-19/metabolism , COVID-19/pathology , COVID-19/virology , Humans , Influenza, Human/complications , Influenza, Human/metabolism , Influenza, Human/virology , Lung/metabolism , Mice, Inbred C57BL , Pneumonia, Viral/etiology , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , T-Lymphocytes, Regulatory/metabolism
15.
Biomolecules ; 11(1)2020 12 24.
Article in English | MEDLINE | ID: covidwho-1067683

ABSTRACT

The medical burden caused by respiratory manifestations of influenza virus (IV) outbreak as an infectious respiratory disease is so great that governments in both developed and developing countries have allocated significant national budget toward the development of strategies for prevention, control, and treatment of this infection, which is seemingly common and treatable, but can be deadly. Frequent mutations in its genome structure often result in resistance to standard medications. Thus, new generations of treatments are critical to combat this ever-evolving infection. Plant materials and active compounds have been tested for many years, including, more recently, active compounds like flavonoids. Quercetin is a compound belonging to the flavonols class and has shown therapeutic effects against influenza virus. The focus of this review includes viral pathogenesis as well as the application of quercetin and its derivatives as a complementary therapy in controlling influenza and its related symptoms based on the targets. We also touch on the potential of this class of compounds for treatment of SARS-COV-2, the cause of new pandemic.


Subject(s)
COVID-19 , Disease Outbreaks , Influenza A virus/metabolism , Influenza, Human , Quercetin/therapeutic use , SARS-CoV-2/metabolism , COVID-19/drug therapy , COVID-19/epidemiology , COVID-19/metabolism , Humans , Influenza, Human/drug therapy , Influenza, Human/epidemiology , Influenza, Human/metabolism
16.
Cell Death Dis ; 12(1): 53, 2021 01 07.
Article in English | MEDLINE | ID: covidwho-1015001

ABSTRACT

Interleukin-38 has recently been shown to have anti-inflammatory properties in lung inflammatory diseases. However, the effects of IL-38 in viral pneumonia remains unknown. In the present study, we demonstrate that circulating IL-38 concentrations together with IL-36α increased significantly in influenza and COVID-19 patients, and the level of IL-38 and IL-36α correlated negatively and positively with disease severity and inflammation, respectively. In the co-cultured human respiratory epithelial cells with macrophages to mimic lung microenvironment in vitro, IL-38 was able to alleviate inflammatory responses by inhibiting poly(I:C)-induced overproduction of pro-inflammatory cytokines and chemokines through intracellular STAT1, STAT3, p38 MAPK, ERK1/2, MEK, and NF-κB signaling pathways. Intriguingly, transcriptomic profiling revealed that IL-38 targeted genes were associated with the host innate immune response to virus. We also found that IL-38 counteracts the biological processes induced by IL-36α in the co-culture. Furthermore, the administration of recombinant IL-38 could mitigate poly I:C-induced lung injury, with reduced early accumulation of neutrophils and macrophages in bronchoalveolar lavage fluid, activation of lymphocytes, production of pro-inflammatory cytokines and chemokines and permeability of the alveolar-epithelial barrier. Taken together, our study indicates that IL-38 plays a crucial role in protection from exaggerated pulmonary inflammation during poly(I:C)-induced pneumonia, thereby providing the basis of a novel therapeutic target for respiratory viral infections.


Subject(s)
COVID-19/metabolism , Immunity, Innate/drug effects , Influenza, Human/metabolism , Interleukins/pharmacology , Pneumonia/prevention & control , Poly I-C/toxicity , Respiratory System/immunology , Animals , COVID-19/immunology , COVID-19/virology , Cytokines/metabolism , Epithelial Cells/immunology , Epithelial Cells/metabolism , Epithelial Cells/pathology , Humans , Influenza A virus/isolation & purification , Influenza, Human/immunology , Influenza, Human/virology , Interleukin-1/blood , Interleukins/blood , Male , Mice , Mice, Inbred C57BL , Pneumonia/chemically induced , Pneumonia/immunology , Pneumonia/pathology , Respiratory System/metabolism , Respiratory System/pathology , SARS-CoV-2/isolation & purification
17.
J Infect Dis ; 224(5): 821-830, 2021 09 01.
Article in English | MEDLINE | ID: covidwho-1006333

ABSTRACT

BACKGROUND: Human spillovers of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to dogs and the emergence of a highly contagious avian-origin H3N2 canine influenza virus have raised concerns on the role of dogs in the spread of SARS-CoV-2 and their susceptibility to existing human and avian influenza viruses, which might result in further reassortment. METHODS: We systematically studied the replication kinetics of SARS-CoV-2, SARS-CoV, influenza A viruses of H1, H3, H5, H7, and H9 subtypes, and influenza B viruses of Yamagata-like and Victoria-like lineages in ex vivo canine nasal cavity, soft palate, trachea, and lung tissue explant cultures and examined ACE2 and sialic acid (SA) receptor distribution in these tissues. RESULTS: There was limited productive replication of SARS-CoV-2 in canine nasal cavity and SARS-CoV in canine nasal cavity, soft palate, and lung, with unexpectedly high ACE2 levels in canine nasal cavity and soft palate. Canine tissues were susceptible to a wide range of human and avian influenza viruses, which matched with the abundance of both human and avian SA receptors. CONCLUSIONS: Existence of suitable receptors and tropism for the same tissue foster virus adaptation and reassortment. Continuous surveillance in dog populations should be conducted given the many chances for spillover during outbreaks.


Subject(s)
COVID-19/virology , Influenza A virus/physiology , Lung/virology , Nasal Cavity/virology , SARS-CoV-2/physiology , Trachea/virology , Viral Tropism/physiology , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/metabolism , Dogs , Humans , Influenza, Human/metabolism , Influenza, Human/virology , Lung/metabolism , Nasal Cavity/metabolism , Orthomyxoviridae Infections/metabolism , Orthomyxoviridae Infections/virology , Trachea/metabolism
18.
Sci Immunol ; 5(53)2020 11 06.
Article in English | MEDLINE | ID: covidwho-999190

ABSTRACT

Lower respiratory viral infections, such as influenza virus and severe acute respiratory syndrome coronavirus 2 infections, often cause severe viral pneumonia in aged individuals. Here, we report that influenza viral pneumonia leads to chronic nonresolving lung pathology and exacerbated accumulation of CD8+ tissue-resident memory T cells (TRM) in the respiratory tract of aged hosts. TRM cell accumulation relies on elevated TGF-ß present in aged tissues. Further, we show that TRM cells isolated from aged lungs lack a subpopulation characterized by expression of molecules involved in TCR signaling and effector function. Consequently, TRM cells from aged lungs were insufficient to provide heterologous protective immunity. The depletion of CD8+ TRM cells dampens persistent chronic lung inflammation and ameliorates tissue fibrosis in aged, but not young, animals. Collectively, our data demonstrate that age-associated TRM cell malfunction supports chronic lung inflammatory and fibrotic sequelae after viral pneumonia.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Immunologic Memory/immunology , Lung/immunology , Pneumonia, Viral/immunology , SARS-CoV-2/immunology , Age Factors , Animals , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/virology , COVID-19/metabolism , COVID-19/virology , Host-Pathogen Interactions/immunology , Humans , Influenza, Human/immunology , Influenza, Human/metabolism , Influenza, Human/virology , Lung/metabolism , Lung/virology , Mice, Inbred C57BL , Orthomyxoviridae/immunology , Orthomyxoviridae/physiology , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/metabolism , Orthomyxoviridae Infections/virology , Pandemics , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , SARS-CoV-2/physiology , Transforming Growth Factor beta/immunology , Transforming Growth Factor beta/metabolism
19.
Cell Prolif ; 54(1): e12953, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-991253

ABSTRACT

OBJECTIVES: Using strategy of drug repurposing, antiviral agents against influenza A virus (IAV) and newly emerging SARS-coronavirus 2 (SARS-CoV-2, also as 2019-nCoV) could be quickly screened out. MATERIALS AND METHODS: A previously reported engineered replication-competent PR8 strain carrying luciferase reporter gene (IAV-luc) and multiple pseudotyped IAV and SARS-CoV-2 virus was used. To specifically evaluate the pH change of vesicles containing IAV, we constructed an A549 cell line with endosomal and lysosomal expression of pHluorin2. RESULTS: Here, we identified azithromycin (AZ) as an effective inhibitor against multiple IAV and SARS-CoV-2 strains. We found that AZ treatment could potently inhibit IAV infection in vitro. Moreover, using pseudotyped virus model, AZ could also markedly block the entry of SARS-CoV-2 in HEK293T-ACE2 and Caco2 cells. Mechanistic studies further revealed that such effect was independent of interferon signalling. AZ treatment neither impaired the binding and internalization of IAV virions, nor the viral replication, but rather inhibited the fusion between viral and vacuolar membranes. Using a NPC1-pHluorin2 reporter cell line, we confirmed that AZ treatment could alkalize the vesicles containing IAV virions, thereby preventing pH-dependent membrane fusion. CONCLUSIONS: Overall, our findings demonstrate that AZ can exert broad-spectrum antiviral effects against IAV and SARS-CoV-2, and could be served as a potential clinical anti-SARS-CoV-2 drug in emergency as well as a promising lead compound for the development of next-generation anti-IAV drugs.


Subject(s)
Antiviral Agents/pharmacology , Azithromycin/pharmacology , COVID-19/metabolism , Influenza A virus/metabolism , Influenza, Human/metabolism , SARS-CoV-2/metabolism , Virus Internalization/drug effects , A549 Cells , COVID-19/drug therapy , COVID-19/genetics , Caco-2 Cells , HEK293 Cells , HeLa Cells , Humans , Influenza A virus/genetics , Influenza, Human/drug therapy , Influenza, Human/genetics , Interferons/genetics , Interferons/metabolism , SARS-CoV-2/genetics , Signal Transduction/drug effects , Signal Transduction/genetics
20.
PLoS One ; 15(12): e0243270, 2020.
Article in English | MEDLINE | ID: covidwho-965212

ABSTRACT

The SARS-CoV-2 (COVID-19) pandemic is a global crisis that threatens our way of life. As of November 18, 2020, SARS-CoV-2 has claimed more than 1,342,709 lives, with a global mortality rate of ~2.4% and a recovery rate of ~69.6%. Understanding the interaction of cellular targets with the SARS-CoV-2 infection is crucial for therapeutic development. Therefore, the aim of this study was to perform a comparative analysis of transcriptomic signatures of infection of SARS-CoV-2 compared to other respiratory viruses (EBOV, H1N1, MERS-CoV, and SARS-CoV), to determine a unique anti-SARS-CoV-2 gene signature. We identified for the first time that molecular pathways for heparin-binding, RAGE, miRNA, and PLA2 inhibitors were associated with SARS-CoV-2 infection. The NRCAM and SAA2 genes, which are involved in severe inflammatory responses, and the FGF1 and FOXO1 genes, which are associated with immune regulation, were found to be associated with the cellular gene response to SARS-CoV-2 infection. Moreover, several cytokines, most significantly IL-8 and IL-6, demonstrated key associations with SARS-CoV-2 infection. Interestingly, the only response gene that was shared among the five viral infections was SERPINB1. The protein-protein interaction (PPI) analysis shed light on genes with high interaction activity that SARS-CoV-2 shares with other viral infections. The findings showed that the genetic pathways associated with rheumatoid arthritis, the AGE-RAGE signaling system, malaria, hepatitis B, and influenza A were of high significance. We found that the virogenomic transcriptome of infection, gene modulation of host antiviral responses, and GO terms of SARS-CoV-2 and EBOV were more similar than to SARS, H1N1, and MERS. This work compares the virogenomic signatures of highly pathogenic viruses and provides valid targets for potential therapy against SARS-CoV-2.


Subject(s)
COVID-19/genetics , SARS-CoV-2/physiology , Transcriptome , COVID-19/metabolism , Coronavirus Infections/genetics , Coronavirus Infections/metabolism , Ebolavirus/physiology , Gene Expression Profiling , Hemorrhagic Fever, Ebola/genetics , Hemorrhagic Fever, Ebola/metabolism , Host-Pathogen Interactions , Humans , Influenza A Virus, H1N1 Subtype/physiology , Influenza, Human/genetics , Influenza, Human/metabolism , Middle East Respiratory Syndrome Coronavirus/physiology , Protein Interaction Maps , SARS Virus/physiology
SELECTION OF CITATIONS
SEARCH DETAIL